4-OXO-3,4-dihydro-1,2,3-benzotriazine modulators of GPR139

ABSTRACT

The present invention provides a method for treating a disease, disorder or condition associated with GPR139 using compounds of formula 1: 
                         
which are agonists of GPR139, certain compounds encompassed by formula 1, pharmaceutical compositions thereof, processes for making the compounds, and intermediates thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/382,490, filed Dec. 16, 2016, now U.S. Pat. No. 9,770,450, which is adivisional of U.S. application Ser. No. 14/946,194, filed Nov. 19, 2015,now U.S. Pat. No. 9,556,130, which claims the benefit of U.S.Provisional Application No. 62/082,539, filed Nov. 20, 2014, and U.S.Provisional Application No. 62/184,729, filed Jun. 25, 2015, which areherein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to medicinal chemistry, pharmacology, andmedicine.

BACKGROUND OF THE INVENTION

GPR139 is an orphan G-protein coupled receptor. GPR139 may be coupledwith Gs, Gq and Gi signaling and appears to be constitutively activewhen recombinantly expressed in mammalian cells. GPR139 is abundantlyexpressed in the CNS (central nervous system) and to a lesser extent inthe pancreas and pituitary and at low levels in other peripheral tissue.

GPR139 is highly conserved among different species. For example, human,mouse, and rat GPR139 protein sequences share greater than 94% identityat the amino acid level. The predominant expression in the brain andhigh degree of sequence homology across different species, suggests thatGPR139 has an important role in physiology.

We have discovered that GPR139 has its strongest expression in themedial habenular nucleus of mice. The habenula receives inputs from thebasal ganglia and the limbic system and sends outputs to midbrain andforebrain structures which contain dopaminergic and serotonergicneurons. Habenular nuclei are involved in pain processing, reproductivebehavior, nutrition, sleep-wake cycles, stress responses, and learning.

In particular, several findings suggested a role of the habenula inschizophrenia. Large calcifications in the pineal and habenula are morecommon in people suffering from schizophrenia than normal controls.Moreover, an fMRI study has shown altered activation of the habenula inpatients with schizophrenia. Also, following an error in a difficultmatching-to-sample task, the habenula was activated in control subjects,but not in patients with schizophrenia. Chronic treatment with cocaineor amphetamine are damaging to the output pathways of the habenula inrats resulting in a schizophrenic-like state.

Thus, modulators of GPR139 are expected to be useful for treatingschizophrenia and other CNS disorders such as depression.

There is a need for treatment of such conditions and others describedherein with compounds that are GPR139 agonists. The present inventionprovides agonists of GPR139 and methods of using GPR139 agonists fortreating diseases, disorders, and conditions associated with GPR139 inthe form of compounds of formula 1 and other embodiments describedherein. Certain activators of GPR139 are described in WO 2014/152917.Certain agonists of GPR139 are described in J. Chem. Inf. Model. 2014,54, 1553-1557 and Med. Chem. Lett. 2011, 2, 303-306. Certain compoundsof formula 1 are commercially available but have no known utility in theCNS.

SUMMARY OF THE INVENTION

The compounds of the invention are agonists of GPR139 and may be usefulfor the treatment of a disease, disorder or condition associated withGPR139.

One aspect of the invention provides a compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein

-   m is selected from 0, 1, and 2;-   n is selected from 0, 1, and 2;-   each R₁ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, and trifluoromethoxy;-   each R₄ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, fluoromethoxy, difluoromethoxy, and    trifluoromethoxy; and-   R₅ is selected from the group consisting of hydrogen,    trifluoromethyl, and C₁₋₄ alkyl, provided:    -   (a) if R₅ is hydrogen, methyl, n-propyl, i-propyl, or i-butyl,        then m and n are not both 0;    -   (b) if R₅ is hydrogen, m is 0, and n is 1, then R₄ is not        chloro, methoxy, 3-trifluoromethyl, 4-trifluoromethyl, 4-methyl,        4-fluoro, 2-difluoromethoxy 3-difluoromethoxy,        2-trifluoromethoxy, 4-trifluoromethoxy, 4-trifluoroethoxy, or        2-(i-butoxy);    -   (c) if R₅ is methyl, m is 0, and n is 1, then R₄ is not chloro,        2-fluoro, 4-fluoro, 2-bromo, 4-ethyl, 2-methyl, 4-(i-propyl),        4-(i-butyl), or 3-trifluoromethyl;    -   (d) if R₅ is ethyl, m is 0, and n is 1, then R₄ is not 3-chloro,        4-chloro, 4-bromo, 4-methyl, 4-methoxy, or 2-difluoromethoxy;    -   (e) if R₅ is n-propyl, m is 0, and n is 1, then R₄ is not        3-trifluoromethyl;    -   (f) if R₅ is i-propyl, m is 0, and n is 1, then R₄ is not        4-fluoro or 4-methoxy;    -   (g) if R₅ is i-butyl, m is 0, and n is 1, then R₄ is not        3-trifluoromethyl;    -   (h) if R₅ is hydrogen, m is 0, and n is 2, then R₄ is not        2,6-difluoro, 2,4-dichloro, 3,5-dimethoxy, 3,4-dimethoxy,        4-methoxy-3-difluoromethoxy, 4-fluoro-2-trifluoromethyl, or        5-bromo-2-difluoromethoxy; and    -   (i) if R₅ is methyl, m is 0, and n is 2, then R₄ is not        3,4-dimethyl, 3,4-dichloro, 2,4-dichloro, 3-fluoro-4-methoxy,        3-bromo-4-methoxy, 3-methoxy-4-isopropyloxy, or        3-methoxy-4-isobutyloxy.        In provisos (b)-(i), each R₄ is attached to a phenyl moiety        having ring carbon atoms consecutively numbered 1 to 6 around        the ring, in which ring carbon atom 1 is attached to an        N-methylacetamide moiety shown in formula 2.

Another aspect of the invention provides a compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein

-   m is selected from 0, 1, and 2;-   n is selected from 0, 1, and 2;-   each R₁ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, and trifluoromethoxy;-   each R₄ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, fluoromethoxy, difluoromethoxy, and    trifluoromethoxy; and-   R₅ is selected from the group consisting of hydrogen,    trifluoromethyl, and C₁₋₄ alkyl, provided the compound of formula 2    is not:-   N-[[2-(2-methylpropoxy)phenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(2,6-difluorophenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(3,5-dimethoxyphenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[[3-(difluoromethoxy)phenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[[3-(difluoromethoxy)-4-methoxyphenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[[5-bromo-2-(difluoromethoxy)phenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[[2-(trifluoromethoxy)phenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[[4-(trifluoromethoxy)phenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   4-oxo-N-[[4-(trifluoromethyl)phenyl]methyl]-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(3-methoxyphenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(3,4-dimethoxyphenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(2,4-dichlorophenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[[3-(trifluoromethyl)phenyl]methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(4-chlorophenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(4-methylphenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(4-methoxyphenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(2-methoxyphenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(3-chlorophenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(2-chlorophenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[(4-fluorophenyl)methyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-(phenylmethyl)-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3,4-dimethylphenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3,4-dichlorophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-((4-(1-methylethyl)phenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(2-methylphenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3-methoxy-4-isobutyloxyphenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3-bromo-4-methoxyphenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3-methoxy-4-isopropyloxyphenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(4-ethylphenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-[4-(2-methylpropyl)phenyl]ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(2,4-dichlorophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(4-fluorophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3-fluoro-4-methoxyphenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(2-fluorophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-[3-(trifluoromethyl)phenyl]ethyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[1-(2-bromophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(4-chlorophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3-chlorophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(2-chlorophenyl)ethyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-(1-phenylethyl)-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(2-difluoromethoxyphenyl)propyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(3-chlorophenyl)propyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[1-(4-chlorophenyl)propyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[1-(4-methoxyphenyl)propyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[1-(4-bromophenyl)propyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[1-[3-(trifluoromethyl)phenyl]butyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-(1-phenylbutyl)-4-oxo-1,2,3-benzotriazine-3 (4H)-acetamide;-   N-(2-methyl-1-phenylpropyl)-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   N-[1-(4-fluorophenyl)-2-methylpropyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[1-(4-methoxyphenyl)-2-methylpropyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[3-methyl-1-[3-(trifluoromethyl)phenyl]butyl]-4-oxo-1,2,3-benzotriazine-3    (4H)-acetamide;-   N-[3-methyl-1-phenylbutyl]-4-oxo-1,2,3-benzotriazine-3(4H)-acetamide;-   2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(4-(2,2,2-trifluoroethoxy)benzyl)acetamide;    or-   2-(4-oxobenzo[d][1,2,3]triazin-3    (4H)-yl)-N-(1-(p-tolyl)propyl)acetamide.    The specific compounds mentioned in this paragraph, which are    defined to be outside the scope of compounds of formula 2, are    commercially available, but are not disclosed as having central    nervous system activity.

A further aspect of the invention provides a compound of formula 3:

or a pharmaceutically acceptable salt thereof, wherein

-   m is selected from 0, 1, and 2;-   n is selected from 0, 1, and 2;-   each R₁ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, and trifluoromethoxy;-   each R₄ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, fluoromethoxy, difluoromethoxy, and    trifluoromethoxy;-   R₅ is selected from the group consisting of hydrogen,    trifluoromethyl, and C₁₋₄ alkyl, provided:    -   (a) if R₅ is hydrogen or C₁₋₄ alkyl, then m and n are not both        0;    -   (b) if R₅ is hydrogen, m is 0, and n is 1, then R₄ is not halo,        C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, difluoromethoxy, or        trifluoromethoxy;    -   (c) if R₅ is C₁₋₄ alkyl, m is 0, and n is 1, then R₄ is not        halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, or        difluoromethoxy;    -   (d) if R₅ is hydrogen, m is 0, and n is 2, then R₄ is not halo,        C₁₋₄ alkoxy, or difluoromethoxy; and    -   (e) if R₅ is C₁₋₄ alkyl, m is 0, and n is 2, then R₄ is not        halo, C₁₋₄ alkyl, trifluoromethyl, difluoromethoxy, or C₁₋₄        alkoxy.

An additional aspect of the invention provides a compound which is(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamideor a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides a compound which is(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamideor a pharmaceutically acceptable salt thereof.

A further aspect of the invention provides a compound which is(S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamideor a pharmaceutically acceptable salt thereof.

An additional aspect of the invention provides a compound which is(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamideor a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt as defined inthe preceding paragraphs, and a pharmaceutically acceptable excipient.

A further aspect of the invention provides a compound orpharmaceutically acceptable salt as defined in the preceding paragraphsfor use as a medicament.

An additional aspect of the invention provides a compound of formula 1,

or a pharmaceutically acceptable salt thereof, for use as a medicament,wherein:

-   m is selected from 0, 1, and 2;-   n is selected from 0, 1, and 2;-   each R₁ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, and trifluoromethoxy;-   R₂ is selected from the group consisting of hydrogen and C₁₋₄ alkyl;-   R₃ is selected from the group consisting of hydrogen and methyl;-   each R₄ is independently selected from the group consisting of    cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,    trifluoromethyl, fluoromethoxy, difluoromethoxy, and    trifluoromethoxy;-   G is selected from the group consisting of —CHR₅—, —CHR₅—CH₂—, and    —CH₂—CHR₅—; and-   R₅ is selected from the group consisting of hydrogen,    trifluoromethyl, and C₁₋₄ alkyl.

Another aspect of the invention provides a compound or pharmaceuticallyacceptable salt as defined in the preceding paragraphs, for use intreating a disease, disorder or condition selected from the groupconsisting of schizophrenia, autism spectrum disorder, sleep disorders,depression, bipolar disorder, cognitive impairment, attention deficithyperactivity disorder, post-traumatic stress disorder, substance abuse,drug addiction, eating disorders, obsessive compulsive disorder, anxietydisorders, pain, and fibromyalgia.

A further aspect of the invention provides a method of treating adisease, disorder or condition associated with GPR139 in a subject, themethod comprising administering an effective amount of a compound orpharmaceutically acceptable salt as defined in the preceding paragraphs.

An additional aspect of the invention provides a method of treating adisease, disorder or condition in a subject, the method comprisingadministering an effective amount of a compound or pharmaceuticallyacceptable salt as defined in the preceding paragraphs, wherein thedisease, disorder or condition is selected from the group consisting ofschizophrenia, autism spectrum disorder, sleep disorders, depression,bipolar disorder, cognitive impairment, attention deficit hyperactivitydisorder, post-traumatic stress disorder, substance abuse, drugaddiction, eating disorders, obsessive compulsive disorder, anxietydisorders, pain, and fibromyalgia.

Another aspect of the invention provides a use of a compound orpharmaceutically acceptable salt as defined in the preceding paragraphs,for the manufacture of a medicament for the treatment of a disease,disorder or condition associated with GPR139.

A further aspect of the invention provides a combination comprising acompound or pharmaceutically acceptable salt as defined in the precedingparagraphs, and at least one additional pharmacologically active agent.

An additional aspect of the invention provides processes from makingGPR139 agonists and intermediates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “C₁₋₄ alkyl” refers to a straight or branched alkyl chain ofone to four carbon atoms.

The term “C₁₋₄ alkoxy” refers to a C₁₋₄ alkyl attached through an oxygenatom.

The terms “halogen” and “halo” refer to chloro, fluoro, bromo or iodo.

The term “pharmaceutically acceptable salt” refers to a salt ofpharmaceutically acceptable organic acids and bases or inorganic acidsand bases, and includes those described in Journal of PharmaceuticalScience, 66, 2-19 (1977). An example is the hydrochloride salt.

The term “amino” refers to —NH₂.

The term “agonist” refers to both full agonists and partial agonists andother agonists.

The term “substantially enantiomerically pure” refers to greater than90% enantiomeric purity for a given stereocenter. Thus, the term“substantially enantiomerically pure” refers to greater than 80% ee(enantiomeric excess). For compounds that exist as stereoisomers, suchstereoisomers may be substantially enantiomerically pure, or preferably,may have greater than 97% enantiomeric purity, or more preferably, mayhave greater than 99% enantiomeric purity at the stereocenter.

The skilled artisan will appreciate that certain of the compounds of theinvention may exist as isomers. All stereoisomers of the compounds ofthe invention, including geometric isomers, enantiomers, anddiastereomers, in any ratio, are contemplated to be within the scope ofthe present invention.

The skilled artisan will appreciate that certain of the compounds of theinvention exist as tautomers. All tautomeric forms the compounds of theinvention are contemplated to be within the scope of the presentinvention.

Compounds of the invention also include all isotopic variations, inwhich at least one atom is replaced by an atom having the same atomicnumber, but an atomic mass different from the atomic mass most commonlyfound in nature.

The terms “the compounds of the invention” and “a compound of theinvention” and the like include the embodiment of formula 1, formula 2,formula 3, and the other more particular embodiments encompassed byformula 1, 2 and 3 described herein, each of the exemplified compoundsdescribed herein, and a pharmaceutically acceptable salt of each ofthese embodiments.

Further embodiments of compounds of the invention are provided below:

(1a) One embodiment relates to compounds of formula 1 wherein G is—CHR₅—.

(1b) One embodiment relates to compounds of formula 1 and embodiment(1a) wherein R₅ is C₁₋₄ alkyl.

(1c) One embodiment relates to compounds of formula 1 and embodiment(1a) wherein R₅ is methyl.

(1d) One embodiment relates to compounds of formula 1 and embodiments(1b) and (1c) wherein the compound is substantially enantiomericallypure and has the stereochemical configuration represented by formula 1A,

(1e) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), and (1d) wherein R₂ is hydrogen.

(1f) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), and (1e) wherein R₃ is hydrogen.

(1g) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1e), and (1f) wherein m is 0.

(1h) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 0.

(1i) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 1 and R₄ is selectedfrom the group consisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

(1j) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 1 and R₄ is selectedfrom the group consisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy,trifluoromethyl, and trifluoromethoxy.

(1k) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 1 and R₄ is selectedfrom the group consisting of cyano, hydroxy, amino, fluoromethoxy, andtrifluoromethoxy.

(1l) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 1 and R₄ istrifluoromethoxy.

(1m) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 2.

(1n) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 2 and R₄, is eachtime taken, independently selected from the group consisting of halo,C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, fluoromethoxy,difluoromethoxy, and trifluoromethoxy.

(1o) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 2 and R₄, is eachtime taken, independently selected from the group consisting of halo,C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, and trifluoromethoxy.

(1p) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 2 and R₄, each timetaken, is independently selected from the group consisting of cyano,hydroxy, amino, trifluoromethyl, fluoromethoxy, difluoromethoxy, andtrifluoromethoxy.

(1q) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), (1f), and (1g) wherein n is 2 and R₄, each timetaken, is independently selected from the group consisting oftrifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

(1r) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), and (1f) wherein m is 1.

(1s) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), and (1f) wherein m is 1 and R₁ is selected fromthe group consisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,and trifluoromethoxy.

(1f) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), and (1f) wherein m is 1 and R₁ is selected fromthe group consisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, andtrifluoromethyl.

(1u) One embodiment relates to compounds of formula 1 and embodiments(1r), (1s), and (1t) wherein n is 0.

(1v) One embodiment relates to compounds of formula 1 and embodiments(1r), (1s), and (1t) wherein n is 1 and R₄ is selected from the groupconsisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

(1w) One embodiment relates to compounds of formula 1 and embodiments(1r), (1s), and (1t) wherein n is 1 and R₄ is selected from the groupconsisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, andtrifluoromethoxy.

(1x) One embodiment relates to compounds of formula 1 and embodiments(1a), (1b), (1c), (1d), and (1f) wherein m is 2.

(1y) One embodiment relates to compounds of formula 1 and embodiment(1x) wherein n is 1 and R₄ is selected from the group consisting ofhalo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, fluoromethoxy,difluoromethoxy, and trifluoromethoxy

(1z). One embodiment relates to compounds of formula 1 and embodiment(1x) wherein n is 2.

(2a) One embodiment relates to compounds of formula 2 wherein R₅ is C₁₋₄alkyl.

(2b) One embodiment relates to compounds formula 2 wherein R₅ isselected from the group consisting of methyl, ethyl, and isopropyl.

(2c) One embodiment relates to compounds of formula 2 wherein R₅ ismethyl.

(2d) One embodiment relates to compounds of formula 2 and embodiments(2a), (2b), and (2c) wherein the compound is substantiallyenantiomerically pure and has the stereochemical configurationrepresented by formula 2A,

(2e) One embodiment relates to compounds of formula 2 and embodiments(2a), (2b), (2c), and (2d) wherein m is 0.

(2f) One embodiment relates to compounds of embodiments (2a), (2b),(2c), (2d), and (2e) wherein n is 1 and R₄ is trifluoromethoxy.

(2j) One embodiment relates to compounds of embodiments (2a), (2b),(2c), (2d), and (2e) wherein n is 2 and R₄, each time taken, isindependently selected from the group consisting of trifluoromethyl,fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

(2k) One embodiment relates to compounds of formula 2 and embodiments(2a), (2b), (2c), and (2d) wherein m is 1.

(2l) One embodiment relates to compounds of formula 2 and embodiments(2a), (2b), (2c), and (2d) wherein m is 2.

(2m) One embodiment relates to compounds of formula 2 and embodiments(2a), (2b), (2c), and (2d) wherein m is 1 and R₁ is selected from thegroup consisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, andtrifluoromethoxy.

(2n) One embodiment relates to compounds of formula 2 and embodiments(2a), (2b), (2c), and (2d) wherein m is 1 and R₁ is selected from thegroup consisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, and trifluoromethyl.

(3a) One embodiment relates to compounds of formula 3 wherein R₅ is C₁₋₄alkyl.

(3b) One embodiment relates to compounds formula 3 wherein R₅ isselected from the group consisting of methyl, ethyl, and isopropyl.

(3c) One embodiment relates to compounds of formula 3 wherein R₅ ismethyl.

(3d) One embodiment relates to compounds of formula 3 and embodiments(3a), (3b), and (3c) wherein the compound is substantiallyenantiomerically pure and has the stereochemical configurationrepresented by formula 3A:

(3e) One embodiment relates to compounds of formula 3 and embodiments(3a), (3b), (3c), and (3d) wherein m is 0.

(3f) One embodiment relates to compounds of formula 3 and embodiments(3a), (3b), (3c), (3d), and (3e) wherein R₅ is hydrogen.

(3g) One embodiment relates to compounds of embodiment (3f) wherein n is1 and R₄ is selected from the group consisting of cyano, hydroxy, amino,and fluoromethoxy.

(3h) One embodiment relates to compounds of embodiment (3f) wherein n is2 and R₄, each time taken, is independently selected from the groupconsisting of cyano, hydroxy, amino, C₁₋₄ alkyl, fluoromethoxy, andtrifluoromethoxy.

(3i) One embodiment relates to compounds of embodiment (3f) wherein n is2 and R₄, each time taken, is independently selected from the groupconsisting of C₁₋₄ alkyl, fluoromethoxy, and trifluoromethoxy.

(3j) One embodiment relates to compounds of embodiment (3f) wherein n is2 and R₄, each time taken, is independently selected from the groupconsisting of C₁₋₄ alkyl and trifluoromethoxy.

(3k) One embodiment relates to compounds of formula 3 and embodiments(3a), (3b), (3c), (3d), and (3e) wherein m is 2.

Another embodiment relates to a pharmaceutically acceptable salt of eachof the above embodiments, specifically, formula 1, formula 2, formula 3,embodiments (1a)-(1z), embodiments (2a)-(2n), and embodiments (3a)-(3k).

Another embodiment relates to a pharmaceutically acceptable salt of eachof the exemplified compounds.

The compounds of the invention can be prepared by a variety ofprocedures, some of which are described below. All substituents, unlessotherwise indicated, are as previously defined. It is understood thatformulae 2 and 3 are encompassed by formula 1 and that the generalprocedures below for preparing compounds of formula 1 are alsoapplicable to preparing compounds of formulae 2 and 3. The products ofeach step can be recovered by conventional methods including extraction,evaporation, precipitation, chromatography, filtration, trituration,crystallization, and the like. The procedures may require protection ofcertain groups, for example hydroxy, amino, or carboxy groups tominimize unwanted reactions. The selection, use, and removal ofprotecting groups are well known and appreciated as standard practice,for example T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Chemistry (John Wiley and Sons, 1991). It is also readilyapparent that specific stereoisomers can be prepared by stereospecificsynthesis using substantially enantiomerically pure starting materialsor by separation of isomers by chromatography, recrystallization, eitherwith or without auxiliaries, or other means.

Scheme A, step a, depicts an amide forming reaction of an appropriatecompound of formula (a) with an appropriate compound of formula (b) togive a compound of formula 1. An appropriate compound of formula (a) isone in which R₁, R₂, and m are as desired in the final compound offormula 1 or give rise to R₁ and R₂ as desired in the final product offormula 1 and X is hydroxyl or a leaving group, such as halo,specifically chloro, or imidazolyl, an activating moiety, a mixedanhydride of another carboxylic acid, such as formic acid, acetic acid,or represents the other part of a symmetrical anhydride formed from twocompounds of formula (a). An appropriate compound of formula (b) is onein which R₃, R₄, G, and n are as desired in the final compound offormula 1 or give rise to R₃ and R₄ as desired in the final product offormula 1. Compounds of formula (a) and (b) are readily prepared byprocedures that are well known in the art and analogously to proceduresspecifically provided herein.

For example, standard amide forming conditions can be used, such asthose using coupling agents, including those used in peptide couplings,such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide(DCC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.If necessary or desired, an additive such as 4-(dimethylamino)pyridine,1-hydroxybenzotriazole, and the like may be used to facilitate thereaction. Such reactions are generally carried out using a base, such asN-methylmorpholine or triethylamine, in a wide variety of suitablesolvents such as DCM, DMF, NMP, dimethylacetamide, THF, and the like.Such amide forming reactions are well understood and appreciated in theart.

It will be recognized by one of ordinary skill in the art that thecompounds in Scheme A can be elaborated in a variety of ways to givecompounds of formula 1. Such reactions include hydrolysis, oxidation,reduction, alkylation, amidations, sulfonations, and the like.

Also, in an optional step, not shown, the compounds of formula 1 bearingacidic or basic groups can be converted to a pharmaceutically acceptablesalt by methods well known and appreciated in the art.

The following examples are intended to be illustrative and non-limiting,and represent specific embodiments of the present invention.

Proton nuclear magnetic resonance (NMR) spectra were obtained for manyof the compounds in the following examples. Characteristic chemicalshifts (8) are given in parts-per-million downfield fromtetramethylsilane using conventional abbreviations for designation ofmajor peaks, including s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet), and br (broad). The following abbreviationsare used for common solvents: CDCl₃ (deuterochloroform), DMSO-d₆(deuterodimethylsulfoxide), and CD₃OD (deuteromethanol or methanol-d₄).The mass spectra were recorded using either electrospray ionization(ESI) or atmospheric pressure chemical ionization.

The examples below were carried out in appropriate vessels and weretypically stirred. Where indicated, products of certain preparations andexamples are purified by mass-triggered HPLC. Where indicated productsof the preparations and examples were purified by the following methods:HPLC Method A: Pump: Shimadzu LC-8A; UV/Vis: SPD-20A; Software:LCsolution. A Phenomenex Gemini® C18, 5 μm, ID 30×100 mm column was usedand eluted with gradients of ACN (containing 0.035% TFA) and water(containing 0.005% TFA). A 10% to 100% ACN gradient was used unlessotherwise indicated. SFC purification: Multigram II Berger SFC;ChiralPak AD-H (5 um, 21×150 mm) column was used and eluted withgradients of liquid CO₂ and isopropanol. After isolation bychromatography, the solvent was removed and the product was obtained byevaporating product containing fractions (e.g., GeneVac™), rotaryevaporator, evacuated flask, lyophilization, etc.

As used herein terms have their using conventional abbreviations, unlessotherwise indicated, for example: room temperature (RT), methanol(MeOH), ethanol (EtOH), isopropanol (IPA), acetonitrile (MeCN or AcCN),tetrahydrofuran (THF), ethyl acetate (EtOAc), dichloromethane (DCM),dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hydrochloric acid(HCl), diisopropylethylamine (DIEA or DIPEA), hydroxybenzotriazole(HOBT), N-(3-dimethylaminopropyl)-N′-ethylcarbonate (EDC), and the like.

PREPARATION 1 2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

To a suspension of 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1 g, 5.52mmol) in water (7.9 mL) was added solution of 2-aminoacetic acid (0.456g, 6.07 mmol) and triethylamine (0.84 mL, 6.07 mmol) in water (3 mL).The reaction mixture was stirred at 40° C. for 1 h then cooled to 0° C.Concentrated HCl (2.8 mL, 33.1 mmol) and sodium nitrite (0.476 g, 6.90mmol) were added slowly. The mixture was allowed to warm to RT over 1 hthen filtered and washed with water to produce the title compound as anoff-white solid (1.103 g, 90%).

PREPARATION 2 2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 8-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (106 mg, 43%).

PREPARATION 3 2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 5-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (64 mg, 26%).

PREPARATION 4 2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (74 mg, 30%).

PREPARATION 5 2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (172 mg, 71%).

PREPARATION 6 2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 7-chloro-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (204 mg, 84%).

PREPARATION 7 2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a yellow solid (167 mg, 69%).

PREPARATION 8 2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (98 mg, 40%).

PREPARATION 9 2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 6-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (91 mg, 37%).

PREPARATION 102-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid

The title compound was prepared in a manner similar to Preparation 1using 6,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (180 mg, 76%).

PREPARATION 11 2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (65 mg, 26%).

PREPARATION 12 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 7-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as an off-white solid (81 mg, 33%).

PREPARATION 13 2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (71 mg, 29%).

PREPARATION 14 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 7-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (236 mg, 78%).

PREPARATION 152-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acid

The title compound was prepared in a manner similar to Preparation 1using 6-(trifluoromethyl)-1H-benzo[d][1,3]oxazine-2,4-dione to give thetitle compound as a tan solid (153 mg, 65%).

PREPARATION 16 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)aceticacid

The title compound was prepared in a manner similar to Preparation 1using 5-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (42 mg, 14%).

PREPARATION 172-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid

The title compound was prepared in a manner similar to Preparation 1using 6,8-dimethyl-1H-benzo[d][1,3]oxazine-2,4-dione to give the titlecompound as a tan solid (185 mg, 76%).

PREPARATION 182-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid

The title compound was prepared in a manner similar to Preparation 1using 8-fluoro-6-methyl-1H-benzo[d][1,3]oxazine-2,4-dione to give thetitle compound as a grey solid (486 mg, 80%).

PREPARATION 192-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetic acid

To a solution of copper(II) chloride (13.49 g, 100 mmol) and tert-butylnitrite (10 mL, 50.2 mmol) in EtOH:MeOH (252 mL, 20:1) was added ethyl2-amino-4,5-dimethylthiophene-3-carboxylate (10 g, 50.2 mmol) at RT. Thereaction mixture was allowed to stir at RT for 2 h. The resultingmixture was poured into water and extracted with EtOAc (3×). The organiclayers were dried, filtered and concentrated. Purification by flashcolumn chromatography eluting with hexanes in EtOAc (100:1-50:1) to giveethyl 4,5-dimethylthiophene-3-carboxylate (8 g, 87%) as an oil.

To a stirred solution of THF (200 mL) was added LiAlH₄ (7.42 g, 195mmol) portion-wise at 0° C. Then, ethyl4,5-dimethylthiophene-3-carboxylate (12 g, 65.1 mmol) was added to thesuspension. The reaction mixture was allowed to stir at RT for 16 h.After completion of the reaction, water (8 mL) was added drop-wise tothe mixture, followed by 15% NaOH solution (8 mL) and additional water(24 mL). Filtration, then purification by flash column chromatographyeluting in hexanes in EtOAc (50:1-30:1) provided(4,5-dimethylthiophen-3-yl) methanol as an oil (8.0 g, 86%).

To a solution of (4,5-dimethylthiophen-3-yl)methanol (4 g, 25.3 mmol) inTHF (60 mL) was added NBS (4.51 g, 25.3 mmol) at RT. The mixture wasstirred at RT for 1 h then partitioned between K₂CO₃ (aq) and EtOAc. Theorganic layer was dried, filtered and concentrated to give(2-bromo-4,5-dimethylthiophen-3-yl)methanol as oil, which was usedwithout further purification (5.2 g, 93%).

To a solution of (2-bromo-4,5-dimethylthiophen-3-yl)methanol (6 g, 27.1mol) in MeOH (100 mL) was added PdCl₂(dppf) (3.97 g, 5.43 mmol) and TEA(18.9 mL, 136 mmol) at RT. The mixture was stirred at 80° C. under COatmosphere (50 psi) for 48 h. The reaction mixture was diluted withMeOH, filtered and concentrated to give the crude product, which waspurified by column eluting with hexanes in EtOAc (10:1-5:1) to givemethyl 3-(hydroxymethyl)-4,5-dimethylthiophene-2-carboxylate as a whitesolid (4 g, 74%).

To a solution of methyl3-(hydroxymethyl)-4,5-dimethylthiophene-2-carboxylate (2.8 g, 13.98mmol) in DCM (40 mL) was added manganese(IV) oxide (12.16 g, 140 mmol)at RT. The reaction mixture was allowed to stir at 40° C. for 16 h. Themixture was diluted with DCM, filtered, and concentrated to providemethyl 3-formyl-4,5-dimethylthiophene-2-carboxylate as a solid (1.6 g,8.07 mmol, 58%) which was used without further purification.

To a solution of methyl 3-formyl-4,5-dimethylthiophene-2-carboxylate(2.8 g, 14.12 mmol) in EtOH (5 mL) was added 85%-hydrazine hydrate (1.6mL, 28.2 mol) at RT. The reaction mixture was allowed to stir at 80° C.for 4 h then cooled to RT. Filtration provided2,3-dimethylthieno[2,3-d]pyridazin-7(6H)-one as a white solid (1.2 g,47%).

To a suspension of 2,3-dimethylthieno[2,3-d]pyridazin-7(6H)-one (1.7 g,9.43 mmol) and K₂CO₃ (2.61 g, 18.87 mmol) in MeCN (50 mL) was addedethyl 2-bromoacetate (1.0 mL, 9.43 mmol) at RT. The mixture was heatedat 80° C. for 16 h. The mixture was poured into water and extracted withEtOAc. The organic layer was dried, filtered and concentrated to givethe crude product, which was purified by flash chromatography elutingwith hexanes in EtOAc (10:1-5:1) to provide ethyl2-(2,3-dimethyl-7-oxothieno [2,3-d]pyridazin-6(7H)-yl)acetate (1.5 g,60% yield) as a white solid.

To a solution of ethyl2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetate (1.5 g,5.63 mmol) in MeOH (30 mL) was added aq sodium hydroxide (7 mL) at RT.The mixture was allowed to stir at RT for 2 h then solvent was removedand the residue was diluted with water and acidified to pH=2-3 with HCl(4M). Filtration provided the title compound as a white solid (1.2 g,89%).

PREPARATION 20 (S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine

n-Butyl lithium (6.17 mL, 9.87 mmol) was added drop-wise at −78° C. to asolution of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (2.13 g, 8.22mmol) in diethyl ether (16.5 mL). The reaction was stirred for 30minutes before drop-wise addition of N-methoxy-N-methylacetamide (1.272g, 12.34 mmol). The reaction was stirred for 5 minutes at −78° C. thenwarmed to room temperature and stirred for 30 minutes. The solution wasquenched with saturated NH₄Cl, extracted with EtOAc, dried with Na₂SO₄,filtered, and concentrated under reduced pressure. Purification by flashsilica gel chromatography, eluting with 10% EtOAc in heptanes provided1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanone as a clear oil (1.118 g,61%).

1-(2-Fluoro-4-(trifluoromethoxy)phenyl)ethanone (500 mg, 2.251 mmol) wasadded to a solution of (S)-2-methylpropane-2-sulfinamide (227 mg, 1.876mmol) and tetraethoxytitanium (1007 mg, 3.75 mmol, 85%) in THF (3.8 mL)at RT. The solution was stirred at 75° C. for 6 hrs and cooled to RT.The solution was then cooled to −60° C. in an ice bath and addeddrop-wise to a suspension of NaBH₄ (284 mg, 7.50 mmol) in THF (2 mL) at−60° C. The mixture was warmed to 0° C. in an ice bath, then methanol (1mL) was added drop-wise until gas evolution no longer occurred. Thesolution was allowed to warm to RT and added to an equal volume ofsaturated NaCl solution. The precipitate was filtered off throughCelite™ and the wet cake was rinsed with EtOAc. Saturated NaCl solutionwas added to the filtrate and the solution was extracted with EtOAc(3×50 mL). The combined organic fractions were dried over anhydrousMgSO₄ then concentrated under reduced pressure. Purification by flashsilica gel chromatography, eluting with 40-80% EtOAc in heptanesprovided(S)-N—((S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamideas a clear oil (304 mg, 50%).

To a flask containing(S)-N—((S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide(350 mg, 1.069 mmol) was added HCl (1.337 mL, 5.35 mmol, 4 M in dioxane)and methanol (2 mL). The mixture was stirred at RT for 30 min thenconcentrated under reduced pressure to provide the title compound as itsHCl salt (245 mg, 88%) as an off-white solid.

PREPARATION 21 (S)-1-(4-chloro-2-methoxyphenyl)propan-2-amine

A solution of 1-(4-chloro-2-methoxyphenyl)propan-2-one (2.7 g, 13.59mmol), (S)-2-methylpropane-2-sulfinamide (4.28 g, 35.3 mmol) andtetraethoxytitanium (4.0 g, 17.65 mmol) in THF (120 mL) was stirred at70° C. for 12 h. The reaction mixture was quenched with sat. NaHCO₃ (50mL) and filtered over a pad of Celite™. The filtrate was concentratedand diluted with H₂O (50 mL) and extracted with EtOAc (2×50 mL). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography, eluting withpetroleum ether in EtOAc (100:1 to 10:1) provided(S,Z)—N-(1-(4-chloro-2-methoxyphenyl)propan-2-ylidene)-2-methylpropane-2-sulfinamide(2.8 g, 68%) as an oil.

To a solution of(S,Z)—N-(1-(4-chloro-2-methoxyphenyl)propan-2-ylidene)-2-methylpropane-2-sulfinamide(3.3 g, 10.93 mmol) in THF (20 mL) was added NaBH₄ (0.620 g, 16.40 mmol)at 0° C. The mixture was allowed to warm to RT and stirred for 2 h. Thereaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc(2×20 mL). The organic layer was dried over Na₂SO₄ and concentrated togive the crude product. Purification by flash column chromatography,eluting with petroleum ether in EtOAc (100:1 to 10:1) provided(S)-N—((R)-1-(4-chloro-2-methoxyphenyl)propan-2-yl)-2-methylpropane-2-sulfinamideas an oil (430 mg, 13% yield).

To a solution of (S)-N—((S)-1-(4-chloro-2-methoxyphenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (1.6 g, 5.27 mmol) in MeOH(10 mL) was added hydrogen chloride (10.5 mL, 42.1 mmol, 4 M in MeOH) at0° C., then the mixture was allowed to warm to RT for 30 min. Theresulting solid was collected by filtration to afford the title compoundas its HCl salt (1.2 g, 97%) as a white solid.

PREPARATION 22 (S)-1-(2-chloro-4-methoxyphenyl)propan-2-amine

To a solution of 1-(2-chloro-4-methoxyphenyl)propan-2-one (4 g, 20.14mmol) in THF (160 mL) was added (S)-2-methylpropane-2-sulfinamide (7.32g, 60.4 mmol) and tetraethoxytitanium (6.89 g, 30.2 mmol), and theresulting mixture was stirred at 70° C. for 12 h. The reaction mixturewas poured into water, and extracted with EtOAc (3×). The combinedorganic layers was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Purification by flash column chromatography, elutingwith petroleum ether in EtOAc (from 10:1 to 2:1) provided(R,Z)—N-(1-(2-chloro-4-methoxyphenyl)propan-2-ylidene)-2-methylpropane-2-sulfinamideas a yellow oil (4.4 g, 72%).

To a solution of(S,Z)—N-(1-(2-chloro-4-methoxyphenyl)propan-2-ylidene)-2-methylpropane-2-sulfinamide(1.0 g, 3.31 mmol) in THF (20 mL) was added NaBH₄ (0.188 g, 4.97 mmol)at −78° C. The reaction was allowed to warm to RT and stirred for 12 h.The reaction mixture was diluted with H₂O (40 mL) and extracted withEtOAc (2×30 mL). The organic layer was dried over Na₂SO₄ andconcentrated. Purification by flash column chromatography eluting withpetroleum ether in EtOAc (20:1 to 1:1) provided(S)-N—((S)-1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-methylpropane-2-sulfinamideas a white solid (560 mg, 56% yield).

To a solution of(S)-N—((S)-1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(470 mg, 1.547 mmol) in MeOH (10 mL) was added hydrogen chloride (3.1mL, 12.37 mmol, 4 M) at 0° C., and the mixture was allowed to warm to RTfor 30 min. The resulting solid was collected by filtration to affordthe title compound as its HCl salt (360 mg, 99% yield) as a white solid.

PREPARATION 23(S)-N-(1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetamide

The title compound was prepared in a manner similar to Preparation 2using 2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetic acidand (S)-1-(2-chloro-4-methoxyphenyl)propan-2-amine, HCl to give thetitle compound as a white solid (26.7 mg, 76%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.04 (d, J=6.8 Hz, 3 H), 2.31 (s, 3 H), 2.52 (s, 3 H),2.70-2.80 (m, 2 H), 3.75 (s, 3 H), 4.01 (dt, J=14.4, 7.0 Hz, 1 H),4.64-4.74 (m, 2 H), 6.86 (dd, J=8.5, 2.7 Hz, 1 H), 6.96-7.00 (m, 1 H),7.23 (d, J=8.8 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1 H), 8.32-8.36 (m, 1 H);ESI-MS m/z [M, M+2]⁺ 420.2, 422.1.

PREPARATION 24(S)-N-(1-(2-chloro-4-hydroxyphenyl)propan-2-yl)-2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetamide

To a 0° C. solution of(S)-N-(1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetamide(200 mg, 0.476 mmol) in DCM (4.8 mL) was added BBr₃ (2.3 mL, 2.381 mmol,1 M in DCM). After stirring for 10 min, the ice bath was removed andstirring continued at RT for 1 h. Saturated NaHCO₃ (5 mL) was added tothe reaction mixture and stirring continued for 30 min. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. Purification by flash columnchromatography, eluting in 70-100% EtOAc in heptanes provided the titlecompound as an off-white solid (20 mg, 10%). ¹H NMR (500 MHz, DMSO-d6) δppm 1.03 (d, J=6.8 Hz, 3 H), 2.31 (s, 3 H), 2.52 (d, J=1.0 Hz, 3 H),2.62-2.78 (m, 2 H), 3.93-4.04 (m, 1 H), 4.64-4.76 (m, 2 H), 6.67 (dd,J=8.3, 2.4 Hz, 1 H), 6.78 (d, J=2.4 Hz, 1 H), 7.10 (d, J=8.3 Hz, 1 H),8.06 (d, J=7.8 Hz, 1 H), 8.34 (s, 1 H), 8.57-8.59 (m, 1 H), 9.67 (s, 1H); ESI-MS m/z [M+H]⁺ 406.1. The title compound can be readily reactedwith ³H₃CI or other like reagents to give(S)-N-(1-(2-chloro-4-[³H]₃methoxyphenyl)propan-2-yl)-2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetamide.

PREPARATION 25 (S)-1-(4-(trifluoromethoxy)phenyl)propan-1-aminehydrochloride

To a mixture of 4-(trifluoromethoxy)benzaldehyde (2 mL, 14.0 mmol) inDCM was added (S)-2-methylpropane-2-sulfinamide (2.55 g, 21.0 mmol) andcopper(II) sulfate (3.35 g, 21.0 mmol). The solution was stirred at 75°C. for 18 hours. Water, DCM, and Celite™ were added to the mixture.After stirring for 10 min, the mixture was filtered through Celite™ andthe filter-cake was washed with DCM. The combined filtrate wasconcentrated under reduced pressure and the residue was purified byflash chromatography (5-10% EtOAc: Heptanes) to give(S,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene) propane-2-sulfinamideas a colorless oil (3.0 g, 73%).

Combined (S,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (1 g, 3.4 mmol) in THF (10 mL) and cooled to −78°C. under nitrogen. Ethylmagnesium chloride (8.5 mL, 8.5 mmol) was addeddropwise. After stirring at −78° C. for 1 hour, saturated ammoniumchloride solution was added and the mixture was allowed to warm to 0° C.before extraction with EtOAc (3×20 mL). The combined organic layers weredried over MgSO₄, filtered and concentrated. Purification by flashchromatography provided(S)-2-methyl-N—((S)-1-(4-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide as an off-white solid (740 mg, 67%).

To a solution of (S)-2-methyl-N—((S)-1-(4-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide (740 mg, 2.3 mmol) in MeOH (2 mL) was addedhydrogen chloride (0.572 mL, 2.3 mmol). The reaction was stirred at RTfor 18 h. Solvent was removed under reduced pressure to provide thetitle compound (580 mg, 99%).

PREPARATION OF 26 (S)-1-(4-(trifluoromethyl)phenyl)propan-1-aminehydrochloride

The title compound was prepared in a manner similar to Preparation 25using 4-(trifluoromethyl)benzaldehyde to give the title compound as anoff-white solid (570 mg, 99%).

EXAMPLE 1(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-phenylethyl)acetamide

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid(15 mg, 0.073 mmol), HOBT (16 mg, 0.102 mmol) and EDC (21 mg, 0.110mmol) was added DMF (244 μL). After stirring at RT for 5 min,(S)-1-phenylethanamine (11 μL, 0.088 mmol) and DIPEA (64 μL, 0.366 mmol)were added. The reaction mixture was allowed to stir at RT for 1 h thenconcentrated under reduced pressure. Purification by flash silica gelchromatography, eluting with 0-70% EtOAc in heptanes provided the titlecompound as a white solid (3.8 mg, 17% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.39 (d, J=6.8 Hz, 3 H), 4.91-4.99 (m, 1 H), 5.08 (s, 2 H),7.22-7.26 (m, 1 H), 7.31-7.38 (m, 4 H), 7.92-7.99 (m, 1 H), 8.12 (td,J=7.8, 1.5 Hz, 1 H), 8.21-8.28 (m, 2 H), 8.80 (d, J=7.8 Hz, 1 H); ESI-MSm/z [M+H]⁺ 309.9.

EXAMPLE 2(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid(15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110mmol) was added DMF (244 μL). After stirring at RT for 5 min,(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) andDIPEA (64, 0.366 mmol) were added. The reaction mixture was allowed tostir at RT for 1 h then water was added (5 mL). The solid was filteredoff and washed with water to yield the title compound as a white solid(20 mg, 71% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.8 Hz, 3H), 4.98 (quin, J=7.1 Hz, 1 H), 5.09 (s, 2 H), 7.33 (d, J=7.8 Hz, 2 H),7.44-7.49 (m, 2 H), 7.93-7.98 (m, 1 H), 8.09-8.15 (m, 1 H), 8.21-8.29(m, 2 H), 8.85 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 393.9.

EXAMPLE 3(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

To a vial containing2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (20 mg,0.085 mmol), HOBT (17 mg, 0.111 mmol) and EDC (24 mg, 0.128 mmol) wasadded DMF (283 μL). After stirring at RT for 5 min,(S)-1-(p-tolyl)ethanamine (15 μL, 0.102 mmol) and DIPEA (74 μL, 0.425mmol) were added. The reaction mixture was allowed to stir at RT for 1 hthen water was added (10 mL). The solid was filtered off and washed withwater to yield the title compound as a white solid (5 mg, 0.014 mmol,16% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3 H),2.27 (s, 3 H), 3.92 (s, 3 H), 4.85-4.93 (m, 1 H), 4.96 (d, J=1.5 Hz, 2H), 7.13 (d, J=7.8 Hz, 2 H), 7.21 (d, J=8.3 Hz, 2 H), 7.44 (d, J=7.8 Hz,1 H), 7.65-7.71 (m, 1 H), 7.96-8.03 (m, 1 H), 8.68 (d, J=7.8 Hz, 1 H);ESI-MS m/z [M+H]⁺ 354.0.

EXAMPLE 4(S)-N-(1-(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid(20 mg, 0.097 mmol), HOBT (21 mg, 0.136 mmol) and EDC (28 mg, 0.146mmol) was added DMF (325 μL). After stirring at RT for 5 min,(S)-1-(4-bromophenyl)ethanamine (17 μL, 0.117 mmol) and DIPEA (85 μL,0.487 mmol) were added. The reaction mixture was allowed to stir at RTfor 18 h. Purification by HPLC Method A provided the title compound as awhite solid (12 mg, 33% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d,J=7.3 Hz, 3 H), 4.86-4.95 (m, 1 H), 5.07 (s, 2 H), 7.26-7.32 (m, 2 H),7.49-7.56 (m, 2 H), 7.92-7.98 (m, 1 H), 8.07-8.15 (m, 1 H), 8.21-8.29(m, 2 H), 8.83 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 386.8, 388.8.

EXAMPLE 5(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(21 mg, 88%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3 H),2.27 (s, 3 H), 4.86-4.94 (m, 1 H), 5.01-5.11 (m, 2 H), 7.14 (d, J=7.8Hz, 2 H), 7.22 (d, J=8.3 Hz, 2 H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1 H),8.08-8.16 (m, 1 H), 8.21-8.29 (m, 2 H), 8.74 (d, J=8.3 Hz, 1 H); ESI-MSm/z [M+H]⁺ 323.0.

EXAMPLE 6(R)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(R)-1-(p-tolyl)ethanamine to give the title compound as a white solid(39.3 mg, 83%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3 H),2.28 (s, 3 H), 4.86-4.95 (m, 1 H), 5.01-5.11 (m, 2 H), 7.14 (d, J=7.8Hz, 2 H), 7.22 (d, J=7.8 Hz, 2 H), 7.92-7.98 (m, 1 H), 8.09-8.15 (m, 1H), 8.21-8.28 (m, 2 H), 8.74 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺323.0.

EXAMPLE 7(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (14 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 3.73 (s, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.01-5.10 (m, 2 H),6.85-6.92 (m, 2 H), 7.23-7.29 (m, 2 H), 7.92-8.00 (m, 1 H), 8.07-8.16(m, 1 H), 8.21-8.28 (m, 2 H), 8.72 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺339.0.

EXAMPLE 8(S)-N-(1-(4-chlorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-chlorophenyl)ethanamine to give the title compound as a whitesolid (10 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.8 Hz, 3H), 4.93 (quin, J=7.1 Hz, 1 H), 5.07 (s, 2 H), 7.33-7.42 (m, 4 H),7.92-7.98 (m, 1 H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1 H), 8.21-8.28 (m, 2H), 8.83 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 342.9, 345.0.

EXAMPLE 9(S)-N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound asa white solid (16.3 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (d,J=6.8 Hz, 3 H), 2.23 (s, 3 H), 2.24 (s, 3 H), 4.98-5.08 (m, 3 H), 6.94(s, 1 H), 7.01 (d, J=7.8 Hz, 1 H), 7.25 (d, J=7.8 Hz, 1 H), 7.92-7.96(m, 1 H), 8.08-8.14 (m, 1 H), 8.20-8.27 (m, 2 H), 8.74 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 337.0.

EXAMPLE 10(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-o-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(o-tolyl)ethanamine to give the title compound as a white solid (1mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3 H), 2.29(s, 3 H), 5.05 (d, J=2.4 Hz, 2 H), 5.09 (t, J=7.3 Hz, 1 H), 7.11-7.16(m, 2 H), 7.19-7.24 (m, 1 H), 7.38 (d, J=7.8 Hz, 1 H), 7.92-7.98 (m, 1H), 8.11 (td, J=7.6, 1.5 Hz, 1 H), 8.21-8.27 (m, 2 H), 8.80 (d, J=7.3Hz, 1 H); ESI-MS m/z [M+H]⁺ 323.0.

EXAMPLE 11(S)-N-(1-(4-ethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-ethoxyphenyl)ethanamine, HCl to give the title compound as awhite solid (19.4 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29-1.33(m, 3 H), 1.37 (d, J=6.8 Hz, 3 H), 3.96-4.04 (m, 2 H), 4.84-4.93 (m, 1H), 5.01-5.10 (m, 2 H), 6.85-6.90 (m, 2 H), 7.21-7.28 (m, 2 H),7.92-7.99 (m, 1 H), 8.08-8.16 (m, 1 H), 8.21-8.29 (m, 2 H), 8.70 (d,J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 353.0.

EXAMPLE 12(S)-N-(1-(2,4-dimethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2,4-dimethoxyphenyl)ethanamine, HCl to give the title compound asa white solid (17.2 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.28 (d,J=6.8 Hz, 3 H), 3.75 (s, 3 H), 3.77 (s, 3 H), 5.06 (s, 2 H), 5.14 (quin,J=7.3 Hz, 1 H), 6.49-6.53 (m, 2 H), 6.49-6.52 (m, 1 H), 6.52 (s, 2 H),7.22 (d, J=7.8 Hz, 1 H), 7.95 (td, J=7.6, 1.5 Hz, 1 H), 8.11 (ddd,J=8.4, 7.2, 1.5 Hz, 1 H), 8.21-8.28 (m, 2 H), 8.62 (d, J=8.3 Hz, 1 H);ESI-MS m/z [M+Na]⁺ 390.9.

EXAMPLE 13(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compoundas a white solid (81 mg, 88%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40-1.43(m, 3 H), 5.01 (quin, J=7.2 Hz, 1 H), 5.10 (s, 2 H), 7.56 (d, J=8.3 Hz,2 H), 7.70 (d, J=8.3 Hz, 2 H), 7.95 (ddd, J=8.1, 7.1, 1.5 Hz, 1 H),8.10-8.14 (m, 1 H), 8.21-8.28 (m, 2 H), 8.91 (d, J=7.3 Hz, 1 H); ESI-MSm/z [M+Na]⁺ 399.3.

EXAMPLE 14(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(23.4 mg, 77%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz, 3 H),2.27 (s, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.06 (s, 2 H), 7.10-7.24 (m,4 H), 7.96-8.03 (m, 2 H), 8.33-8.39 (m, 1 H), 8.73 (d, J=7.8 Hz, 1 H);ESI-MS m/z [M+H]⁺ 341.0.

EXAMPLE 15(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (18.6 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz,3 H), 3.73 (s, 3 H), 4.90 (quin, J=7.1 Hz, 1 H), 5.05 (d, J=1.0 Hz, 2H), 6.86-6.91 (m, 2 H), 7.22-7.29 (m, 2 H), 7.96-8.03 (m, 2 H),8.33-8.39 (m, 1 H), 8.70 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 357.0.

EXAMPLE 16 (S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as an off-whitesolid (13.0 mg, 43%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz,3 H), 2.27 (s, 3 H), 4.90 (quin, J=7.1 Hz, 1 H), 5.06-5.09 (m, 2 H),7.13 (d, J=7.8 Hz, 2 H), 7.19-7.23 (m, 2 H), 7.91-8.03 (m, 2 H),8.04-8.09 (m, 1 H), 8.73 (d, J=8.3 Hz, 1 H); ESI-MS m/z [M+H]⁺ 341.0.

EXAMPLE 17(S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as anoff-white solid (22.4 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d,J=6.8 Hz, 3 H), 3.73 (s, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.07 (s, 2H), 6.86-6.91 (m, 2 H), 7.23-7.27 (m, 2 H), 7.92-8.03 (m, 2 H), 8.06(dd, J=7.8, 1.5 Hz, 1 H), 8.70 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺357.0.

EXAMPLE 18(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as an off-whitesolid (18.1 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.32-1.40 (m, 3H), 2.27 (s, 3 H), 3.97 (s, 3 H), 4.90 (quin, J=7.3 Hz, 1 H), 5.03 (d,J=1.5 Hz, 2 H), 7.13 (d, J=7.8 Hz, 2 H), 7.22 (d, J=8.3 Hz, 2 H), 7.58(d, J=2.4 Hz, 1 H), 7.63-7.68 (m, 1 H), 8.17 (d, J=8.8 Hz, 1 H), 8.71(d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 353.0.

EXAMPLE 19 (S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as an off-whitesolid (15.6 mg, 52%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz,3 H), 2.25-2.28 (m, 3 H), 4.86-4.94 (m, 1 H), 5.06 (s, 2 H), 7.13 (d,J=7.8 Hz, 2 H), 7.19-7.24 (m, 2 H), 8.13-8.18 (m, 1 H), 8.23 (d, J=2.4Hz, 1 H), 8.27 (d, J=8.3 Hz, 1 H), 8.73 (d, J=7.8 Hz, 1 H); ESI-MS m/z[M, M+2]⁺ 357.0, 358.9.

EXAMPLE 20(S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as anoff-white solid (20.4 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d,J=6.8 Hz, 3 H), 3.70-3.75 (m, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.05 (d,J=1.0 Hz, 2 H), 6.86-6.91 (m, 2 H), 7.22-7.27 (m, 2 H), 8.13-8.18 (m, 1H), 8.23 (d, J=2.4 Hz, 1 H), 8.27 (d, J=8.8 Hz, 1 H), 8.70 (d, J=7.8 Hz,1 H); ESI-MS m/z [M, M+2]⁺ 372.4, 374.9.

EXAMPLE 21(S)-2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as an white solid(15.3 mg, 51%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3 H),2.27 (s, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.06 (s, 2 H), 7.13 (d, J=7.8Hz, 2 H), 7.21 (d, J=7.8 Hz, 2 H), 7.98 (dd, J=8.5, 2.2 Hz, 1 H), 8.25(d, J=8.3 Hz, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 8.73 (d, J=7.8 Hz, 1 H);ESI-MS m/z [M, M+2]⁺ 357.0, 358.9.

EXAMPLE 22(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as an off-whitesolid (18.6 mg, 63%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz,3 H), 2.26-2.29 (m, 3 H), 4.91 (quin, J=7.1 Hz, 1 H), 5.07 (s, 2 H),7.13 (d, J=7.8 Hz, 2 H), 7.19-7.24 (m, 2 H), 7.91 (t, J=7.8 Hz, 1 H),8.17-8.26 (m, 2 H), 8.73 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 357.0,358.9.

EXAMPLE 23(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as anoff-white solid (14.2 mg, 46%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d,J=6.8 Hz, 3 H), 3.71-3.75 (m, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.07 (s,2 H), 6.86-6.91 (m, 2 H), 7.22-7.27 (m, 2 H), 7.87-7.94 (m, 1 H), 8.22(ddd, J=18.4, 7.9, 1.5 Hz, 2 H), 8.70 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M,M+2]⁺ 372.9, 374.9.

EXAMPLE 24(S)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(8.0 mg, 26%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3 H),2.27 (s, 3 H), 2.77 (s, 3 H), 4.90 (t, J=7.6 Hz, 1 H), 5.05 (d, J=1.5Hz, 2 H), 7.13 (d, J=8.3 Hz, 2 H), 7.19-7.24 (m, 2 H), 7.78-7.85 (m, 1H), 7.91-7.96 (m, 1 H), 8.04-8.10 (m, 1 H), 8.72 (d, J=8.3 Hz, 1 H);ESI-MS m/z [M+H]⁺ 337.0.

EXAMPLE 25(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (6.0 mg, 19%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz,3 H), 2.77 (s, 3 H), 3.71-3.75 (m, 3 H), 4.90 (quin, J=7.3 Hz, 1 H),5.04 (d, J=2.4 Hz, 2 H), 6.86-6.92 (m, 2 H), 7.21-7.28 (m, 2 H),7.78-7.85 (m, 1 H), 7.94 (dt, J=7.1, 1.3 Hz, 1 H), 8.07 (d, J=7.3 Hz, 1H), 8.70 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 353.0.

EXAMPLE 26(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(12.1 mg, 42%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3 H),2.27 (s, 3 H), 4.86-4.94 (m, 1 H), 5.07 (s, 2 H), 7.13 (d, J=7.8 Hz, 2H), 7.19-7.23 (m, 2 H), 8.20 (d, J=2.0 Hz, 1 H), 8.44-8.47 (m, 1 H),8.72 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 390.8, 392.9.

EXAMPLE 27(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (16.2 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz,3 H), 3.71-3.75 (m, 3 H), 4.86-4.93 (m, 1 H), 5.07 (d, J=1.0 Hz, 2 H),6.87-6.91 (m, 2 H), 7.22-7.28 (m, 2 H), 8.18-8.22 (m, 1 H), 8.45 (d,J=2.4 Hz, 1 H), 8.70 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 406.8,408.8.

EXAMPLE 28(S)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(9.1 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3 H),2.27 (s, 3 H), 2.55 (s, 3 H), 4.90 (t, J=7.6 Hz, 1 H), 5.04 (d, J=1.5Hz, 2 H), 7.11-7.16 (m, 2 H), 7.22 (d, J=7.8 Hz, 2 H), 7.92 (dd, J=8.3,1.5 Hz, 1 H), 8.05 (s, 1 H), 8.12 (d, J=8.3 Hz, 1 H), 8.71 (d, J=7.8 Hz,1 H); ESI-MS m/z [M+H]⁺ 337.1.

EXAMPLE 29(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as anoff-white solid (7.0 mg, 22%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d,J=6.8 Hz, 3 H), 2.54-2.57 (m, 3 H), 3.73 (s, 3 H), 4.89 (quin, J=7.2 Hz,1 H), 5.03 (d, J=2.0 Hz, 2 H), 6.86-6.91 (m, 2 H), 7.23-7.27 (m, 2 H),7.93 (dd, J=8.3, 1.5 Hz, 1 H), 8.05 (s, 1 H), 8.12 (d, J=8.3 Hz, 1 H),8.69 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 353.0.

EXAMPLE 30(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(12.3 mg, 41%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3 H),2.26-2.28 (m, 3 H), 4.04 (s, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.03 (s,2 H), 7.13 (d, J=7.8 Hz, 2 H), 7.21 (d, J=8.3 Hz, 2 H), 7.64 (dd, J=8.3,1.0 Hz, 1 H), 7.72-7.76 (m, 1 H), 7.85-7.90 (m, 1 H), 8.71 (d, J=7.8 Hz,1 H); ESI-MS m/z [M+H]⁺ 353.0.

EXAMPLE 31 (S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (11.8 mg, 38%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz,3 H), 3.72-3.74 (m, 3 H), 4.04 (s, 3 H), 4.89 (quin, J=7.2 Hz, 1 H),4.99-5.05 (m, 2 H), 6.86-6.91 (m, 2 H), 7.21-7.27 (m, 2 H), 7.64 (dd,J=8.3, 1.0 Hz, 1 H), 7.71-7.77 (m, 1 H), 7.84-7.90 (m, 1 H), 8.68 (d,J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 369.0.

EXAMPLE 32(S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(11.3 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3 H),2.24-2.29 (m, 4 H), 4.87-4.95 (m, 1 H), 5.02 (s, 2 H), 7.11-7.15 (m, 2H), 7.21 (d, J=8.3 Hz, 2 H), 7.71-7.78 (m, 1 H), 8.03-8.14 (m, 2H), 8.71(d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 341.0.

EXAMPLE 33(S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(8.4 mg, 26%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3 H),3.71-3.75 (m, 3 H), 4.84-4.95 (m, 1 H), 5.01 (s, 2 H), 6.86-6.92 (m, 2H), 7.22-7.28 (m, 2 H), 7.71-7.79 (m, 1 H), 8.04-8.08 (m, 1 H),8.08-8.15 (m, 1 H), 8.69 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 356.9.

EXAMPLE 34(S)-2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(28.2 mg, 92%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz, 3 H),2.27 (s, 3 H), 2.57 (s, 3 H), 4.90 (t, J=7.3 Hz, 1 H), 5.04 (d, J=1.0Hz, 2 H), 7.10-7.16 (m, 2 H), 7.20-7.23 (m, 2 H), 7.77 (d, J=7.8 Hz, 1H), 8.04 (s, 1 H), 8.13 (d, J=7.8 Hz, 1 H), 8.72 (d, J=7.8 Hz, 1 H);ESI-MS m/z [M+Na]⁺ 359.0.

EXAMPLE 35(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (24.1 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.00-0.00 (m, 1H), 1.36 (d, J=6.8 Hz, 3 H), 2.56-2.59 (m, 3 H), 3.73 (s, 3 H), 4.89(quin, J=7.2 Hz, 1 H), 5.03 (d, J=2.0 Hz, 2 H), 6.86-6.91 (m, 2 H),7.23-7.27 (m, 2 H), 7.75-7.80 (m, 1 H), 8.04 (s, 1 H), 8.14 (d, J=8.3Hz, 1 H), 8.66-8.73 (m, 1 H); ESI-MS m/z [M+H]⁺ 353.0.

EXAMPLE 36(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(23.3 mg, 78%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.32-1.40 (m, 3 H), 2.27(s, 3 H), 3.99 (s, 3 H), 4.89 (quin, J=7.3 Hz, 1 H), 5.03 (d, J=1.0 Hz,2 H), 7.13 (d, J=7.8 Hz, 2 H), 7.22 (d, J=7.8 Hz, 2 H), 7.49 (dd, J=8.8,2.4 Hz, 1 H), 7.66 (d, J=2.9 Hz, 1 H), 8.14 (d, J=8.8 Hz, 1 H), 8.72 (d,J=8.3 Hz, 1 H); ESI-MS m/z [M+H]⁺ 353.0.

EXAMPLE 37(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (20.6 mg, 66%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=7.3 Hz,3 H), 3.71-3.74 (m, 3 H), 3.99 (s, 3 H), 4.89 (quin, J=7.2 Hz, 1 H),5.02 (d, J=1.5 Hz, 2 H), 6.86-6.91 (m, 2 H), 7.22-7.27 (m, 2 H), 7.49(dd, J=8.8, 2.4 Hz, 1 H), 7.66 (d, J=2.4 Hz, 1 H), 8.11-8.18 (m, 1 H),8.69 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 369.0.

EXAMPLE 38 (S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (4.2 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.8 Hz,3 H), 3.70-3.74 (m, 3 H), 3.92 (s, 3 H), 4.83-4.92 (m, 1 H), 4.95 (d,J=2.0 Hz, 2 H), 6.85-6.91 (m, 2 H), 7.25 (d, J=8.8 Hz, 2 H), 7.44 (d,J=7.8 Hz, 1 H), 7.67-7.71 (m, 1 H), 7.96-8.04 (m, 1 H), 8.65 (d, J=8.3Hz, 1 H); ESI-MS m/z [M+H]⁺ 369.0.

EXAMPLE 39 (S)-2-(5-methyl-4-oxobenzo[d] [1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(1.2 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.34-1.39 (m, 3 H),2.26-2.29 (m, 4 H), 2.81 (s, 3 H), 4.85-4.94 (m, 1 H), 5.00 (s, 2 H),7.13 (d, J=7.8 Hz, 2 H), 7.19-7.25 (m, 2 H), 7.70 (d, J=7.3 Hz, 1 H),7.91-7.98 (m, 1 H), 8.02 (d, J=8.3 Hz, 1 H), 8.71 (d, J=7.8 Hz, 1 H);ESI-MS m/z [M+Na]⁺ 359.0.

EXAMPLE 40(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (0.5 mg, 2%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=7.3 Hz, 3H), 2.81 (s, 3 H), 3.72-3.75 (m, 3 H), 4.86-4.94 (m, 1 H), 4.99 (s, 2H), 6.85-6.93 (m, 2 H), 7.23-7.29 (m, 2 H), 7.68-7.74 (m, 1 H),7.91-7.97 (m, 1 H), 7.99-8.05 (m, 1 H), 8.68 (d, J=8.3 Hz, 1 H); ESI-MSm/z [M+Na]⁺ 375.0.

EXAMPLE 41(S)-2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(p-tolyl)ethanamine to give the title compound as a white solid(10.7 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz, 3 H),2.28 (s, 3 H), 2.73 (s, 3 H), 4.90 (quin, J=7.3 Hz, 1 H), 5.03 (d, J=2.4Hz, 2 H), 7.13 (d, J=8.3 Hz, 2 H), 7.20-7.23 (m, 2 H), 7.77 (s, 1 H),7.87 (s, 1 H), 8.71 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 351.1.

EXAMPLE 42(S)-2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)ethanamine to give the title compound as a whitesolid (9.0 mg, 29%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz,3 H), 2.29 (d, J=2.4 Hz, 1 H), 2.73 (s, 3 H), 3.73 (s, 3 H), 4.90 (quin,J=7.2 Hz, 1 H), 5.02 (d, J=2.9 Hz, 2 H), 6.86-6.91 (m, 2 H), 7.23-7.27(m, 2 H), 7.75-7.79 (m, 1 H), 7.88 (d, J=1.0 Hz, 1 H), 8.69 (d, J=7.8Hz, 1 H); ESI-MS m/z [M+H]⁺ 367.0.

EXAMPLE 43(S)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acidand (S)-1-(p-tolyl)ethanamine to give the title compound as a whitesolid (16.8 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz,3 H), 2.26-2.28 (m, 3 H), 4.91 (t, J=7.6 Hz, 1 H), 5.11 (s, 2 H), 7.14(d, J=7.8 Hz, 2 H), 7.20-7.25 (m, 2 H), 8.41-8.53 (m, 3 H), 8.75 (d,J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 391.0.

EXAMPLE 44(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3(4H)-yl)acetic acidand (S)-1-(4-methoxyphenyl)ethanamine to give the title compound as awhite solid (20.3 mg, 68%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d,J=6.8 Hz, 3 H), 3.73 (s, 3 H), 4.86-4.95 (m, 1 H), 5.10 (d, J=1.0 Hz, 2H), 6.84-6.93 (m, 2 H), 7.23-7.27 (m, 2 H), 8.41-8.54 (m, 3 H), 8.72 (d,J=8.3 Hz, 1 H); ESI-MS m/z [M+Na]⁺ 429.0.

EXAMPLE 45(S)-2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(p-tolyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acidand (S)-1-(p-tolyl)ethanamine to give the title compound as a whitesolid (25.5 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.37 (d, J=6.8 Hz,3 H), 2.27 (s, 3 H), 2.55 (s, 3 H), 4.90 (quin, J=7.2 Hz, 1 H), 5.06 (s,2 H), 7.13 (d, J=7.8 Hz, 2 H), 7.22 (d, J=7.8 Hz, 2 H), 7.83-7.90 (m, 2H), 8.72 (d, J=8.3 Hz, 1 H); ESI-MS m/z [M+H]⁺ 355.4.

EXAMPLE 46(S)-N-(1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-methoxy-4-methylphenyl)ethanamine, HCl to give the titlecompound as a tan solid (38.8 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.29 (d, J=6.8 Hz, 3 H), 2.28 (s, 3 H), 3.77 (s, 3 H), 5.03-5.08 (m, 2H), 5.16 (quin, J=7.2 Hz, 1 H), 6.75 (d, J=7.8 Hz, 1 H), 6.78 (s, 1 H),7.19 (d, J=7.8 Hz, 1 H), 7.92-7.98 (m, 1 H), 8.08-8.15 (m, 1 H),8.20-8.28 (m, 2 H), 8.66 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 353.2.

EXAMPLE 47(S)-N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-chloro-4-fluorophenyl)ethanamine, HCl to give the titlecompound as a white solid (30.1 mg, 57%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.36 (d, J=6.8 Hz, 3 H), 5.09 (s, 2 H), 5.19 (quin, J=7.1 Hz, 1 H),7.27 (td, J=8.5, 2.9 Hz, 1 H), 7.39 (dd, J=8.8, 2.9 Hz, 1 H), 7.54 (dd,J=8.8, 6.3 Hz, 1 H), 7.90-7.99 (m, 1 H), 8.11 (td, J=7.6, 1.5 Hz, 1 H),8.21-8.27 (m, 2 H), 8.97 (d, J=7.3 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 360.1,362.1.

EXAMPLE 48(S)-N-(1-(2-bromo-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-bromo-4-fluorophenyl)ethanamine, HCl to give the title compoundas a white solid (37.4 mg, 63%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35(d, J=7.3 Hz, 3 H), 5.09 (s, 2 H), 5.11-5.19 (m, 1 H), 7.32 (td, J=8.5,2.4 Hz, 1 H), 7.49-7.56 (m, 2 H), 7.92-7.98 (m, 1 H), 8.11 (td, 1.5 Hz,1 H), 8.20-8.28 (m, 2 H), 9.00 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M, M+2]⁺405.1, 407.1.

EXAMPLE 49(S)-N-(1-(4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-fluorophenyl)ethanamine to give the title compound as a whitesolid (27.9 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36-1.41 (m, 3H), 4.95 (quin, J=7.2 Hz, 1 H), 5.07 (s, 2 H), 7.12-7.21 (m, 2 H),7.35-7.41 (m, 2 H), 7.92-7.99 (m, 1 H), 8.08-8.15 (m, 1 H), 8.20-8.29(m, 2 H), 8.79 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 327.2.

EXAMPLE 50(S)-N—((S)-1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)propanamide

and

EXAMPLE 51(R)—N((S)-1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-propanamide

To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)propanoicacid (50 mg, 0.228 mmol), HOBT (45 mg, 0.297 mmol) and EDC (66 mg, 0.342mmol) was added DMF (760 μL). After stirring at RT for 5 min,(S)-1-(2-methoxy-4-methylphenyl)ethanamine, HCl (55 mg, 0.274 mmol) andDIPEA (240 μL, 1.369 mmol) were added. The reaction mixture was allowedto stir at RT for 1 h then water was added (10 mL). The solid wasfiltered off and washed with water, then dried to provide a tan solid.Purification by SFC gave the title compounds as white solids. Retentiontime 1.62 min: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.25 (d, J=6.8 Hz, 3 H),1.70-1.77 (m, 3 H), 2.26 (s, 2 H), 3.13-3.19 (m, 3 H), 3.75 (s, 4 H),5.13 (quin, J=7.1 Hz, 1 H), 5.60 (q, J=7.3 Hz, 1 H), 6.70 (d, J=7.3 Hz,1 H), 6.76 (s, 1 H), 7.14 (d, J=7.3 Hz, 1 H), 7.89-7.96 (m, 1 H),8.08-8.14 (m, 1 H), 8.20-8.27 (m, 2 H), 8.49 (d, J=7.8 Hz, 1 H); ESI-MSm/z [M+H]⁺ 367.2; Retention time 2.72 min: ¹H NMR (500 MHz, DMSO-d₆) δppm 1.26 (d, J=6.8 Hz, 3 H), 1.73 (d, J=7.3 Hz, 3 H), 2.28 (s, 3 H),3.76 (s, 3 H), 5.14 (quin, J=7.2 Hz, 1 H), 5.53-5.60 (m, 1 H), 6.74 (d,J=7.8 Hz, 1 H), 6.78 (s, 1 H), 7.13 (d, J=7.3 Hz, 1 H), 7.90-7.98 (m, 1H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1 H), 8.22 (d, J=7.8 Hz, 1 H), 8.26(dd, J=7.8, 1.0 Hz, 1 H), 8.52 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺367.2.

EXAMPLE 52(S)-N-(1-(2,4-dimethylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2,4-dimethylphenyl)ethanamine, HCl to give the title compound asa white solid (23.6 mg, 74%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (d,J=6.8 Hz, 3 H), 2.23 (s, 3 H), 2.24 (s, 3 H), 4.99-5.08 (m, 3 H), 6.94(s, 1 H), 7.01 (d, J=7.8 Hz, 1 H), 7.25 (d, J=7.8 Hz, 1 H), 7.97-8.03(m, 2 H), 8.35 (dd, J=8.8, 4.9 Hz, 1 H), 8.73 (d, J=7.8 Hz, 1 H); ESI-MSm/z [M+H]⁺ 355.3.

EXAMPLE 53(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the titlecompound as a white solid (23.4 mg, 71%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.37 (d, J=7.3 Hz, 3 H), 2.29 (s, 3 H), 5.05-5.16 (m, 3 H),6.93-7.03 (m, 2 H), 7.31 (t, J=8.1 Hz, 1 H), 7.91-7.99 (m, 1 H), 8.11(td, J=7.6, 1.5 Hz, 1 H), 8.20-8.28 (m, 2 H), 8.83 (d, J=7.3 Hz, 1 H);ESI-MS m/z [M+H]⁺ 341.2.

EXAMPLE 54(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-fluoro-4-methylphenyl)ethanamine, HCl to give the titlecompound as a white solid (13.6 mg, 42%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.37 (d, J=6.8 Hz, 3 H), 2.29 (s, 3 H), 5.05-5.14 (m, 3 H),6.91-7.04 (m, 2 H), 7.30 (t, J=8.1 Hz, 1 H), 7.97-8.04 (m, 2 H), 8.36(dd, J=8.5, 5.1 Hz, 1 H), 8.84 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺359.2.

EXAMPLE 55(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compoundas a white solid (13.2 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.37-1.42 (m, 3 H), 4.97 (quin, J=7.1 Hz, 1 H), 5.08 (s, 2 H), 7.30-7.35(m, 2 H), 7.42-7.47 (m, 2 H), 7.97-8.03 (m, 2 H), 8.33-8.40 (m, 1 H),8.85 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 411.2.

EXAMPLE 56(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compoundas a white solid (21.8 mg, 81%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40(d, J=6.8 Hz, 3 H), 3.99 (s, 3 H), 4.97 (quin, J=7.2 Hz, 1 H), 5.06 (s,2 H), 7.33 (d, J=8.3 Hz, 2 H), 7.44-7.52 (m, 3 H), 7.67 (d, J=2.4 Hz, 1H), 8.15 (d, J=9.3 Hz, 1 H), 8.84 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺423.4.

EXAMPLE 57(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compoundas a white solid (17.3 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40(d, J=6.8 Hz, 3 H), 3.98 (s, 3 H), 4.97 (quin, J=7.1 Hz, 1 H), 5.06 (s,2 H), 7.33 (d, J=7.8 Hz, 2 H), 7.44-7.49 (m, 2 H), 7.58 (d, J=2.9 Hz, 1H), 7.64-7.69 (m, 1 H), 8.17 (d, J=8.8 Hz, 1 H), 8.83 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

EXAMPLE 58(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compoundas a white solid (16.2 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40(d, J=7.3 Hz, 3 H), 3.93 (s, 3 H), 4.93-5.00 (m, 3 H), 7.33 (d, J=8.3Hz, 2 H), 7.43-7.48 (m, 3 H), 7.65-7.72 (m, 1 H), 8.00 (t, J=8.3 Hz, 1H), 8.79 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 423.3.

EXAMPLE 59 (S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compoundas a white solid (22.5 mg, 87%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41(d, J=6.8 Hz, 3 H), 3.99 (s, 3 H), 5.00 (quin, J=7.1 Hz, 1 H), 5.07 (s,2 H), 7.49 (dd, J=8.8, 2.9 Hz, 1 H), 7.56 (d, J=8.3 Hz, 2 H), 7.67 (d,J=2.9 Hz, 1 H), 7.70 (d, J=8.8 Hz, 2 H), 8.15 (d, J=8.8 Hz, 1 H), 8.91(d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 407.4.

EXAMPLE 60(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compoundas a white solid (19.9 mg, 77%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.42(d, J=6.8 Hz, 3 H), 3.97 (s, 3 H), 4.97-5.03 (m, 1 H), 5.07 (s, 2 H),7.54-7.58 (m, 3 H), 7.65 (dd, J=9.0, 2.7 Hz, 1 H), 7.70 (d, J=7.8 Hz, 2H), 8.17 (d, J=9.3 Hz, 1 H), 8.90 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺407.4.

EXAMPLE 61 (S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compoundas a white solid (12.9 mg, 50%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41(d, J=7.3 Hz, 3 H), 3.93 (s, 3 H), 4.96-5.04 (m, 3 H), 7.41-7.47 (m, 1H), 7.56 (d, J=8.3 Hz, 2 H), 7.66-7.73 (m, 3 H), 7.99 (t, J=8.3 Hz, 1H), 8.86 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 407.4.

EXAMPLE 62(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine to give the title compoundas a white solid (4.8 mg, 18%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.39 (d,J=7.3 Hz, 3 H), 4.04 (s, 3 H), 4.97 (quin, J=7.1 Hz, 1 H), 5.06 (s, 2H), 7.33 (d, J=8.3 Hz, 2 H), 7.43-7.49 (m, 2 H), 7.62-7.67 (m, 1 H),7.74 (dd, J=7.8, 1.0 Hz, 1 H), 7.84-7.91 (m, 1 H), 8.82 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 423.3.

EXAMPLE 63 (S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 4 using2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compoundas a white solid (2.6 mg, 10%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41 (d,J=6.8 Hz, 3 H), 4.04 (s, 3 H), 5.00 (quin, J=7.3 Hz, 1 H), 5.07 (s, 2H), 7.56 (d, J=8.3 Hz, 2 H), 7.65 (d, J=8.3 Hz, 1 H), 7.70 (d, J=8.3 Hz,2 H), 7.74 (dd, J=8.1, 1.2 Hz, 1 H), 7.84-7.90 (m, 1 H), 8.89 (d, J=7.8Hz, 1 H); ESI-MS m/z [M+H]⁺ 407.3.

EXAMPLE 64(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(trifluoromethyl)phenyl)ethanamine to give the title compoundas a white solid (10.6 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.41(d, J=7.3 Hz, 3 H), 4.97-5.05 (m, 1 H), 5.10 (s, 2 H), 7.56 (d, J=7.8Hz, 2 H), 7.70 (d, J=8.3 Hz, 2 H), 7.97-8.02 (m, 2 H), 8.36 (ddq, J=8.2,4.9, 1.5, 1.5, 1.5 Hz, 1 H), 8.92 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺395.3.

EXAMPLE 65(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the titlecompound as a white solid (11.3 mg, 60%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.42 (d, J=6.8 Hz, 3 H), 5.10 (s, 2 H), 5.14-5.21 (m, 1 H),7.59-7.70 (m, 3 H), 7.92-7.98 (m, 1 H), 8.11 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.21-8.27 (m, 2 H), 9.02 (d, J=7.3 Hz, 1 H); ESI-MS m/z [M+H]⁺395.6.

EXAMPLE 66(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the titlecompound as a white solid (19.2 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.35-1.40 (m, 3 H), 4.88-4.99 (m, 1 H), 5.03-5.09 (m, 2 H),7.03-7.36 (m, 3 H), 7.14 (d, J=8.8 Hz, 2 H), 7.39 (d, J=8.8 Hz, 2 H),7.95-7.98 (m, 1 H), 8.08-8.15 (m, 1 H), 8.21-8.28 (m, 2 H), 8.81 (d,J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 375.7.

EXAMPLE 67(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine to give the titlecompound as a white solid (15.0 mg, 73%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.42 (d, J=6.8 Hz, 3 H), 3.92 (s, 3 H), 4.97-5.02 (m, 2 H), 5.16(quin, J=7.1 Hz, 1 H), 7.44 (d, J=8.3 Hz, 1 H), 7.57-7.72 (m, 4 H), 7.99(t, J=8.1 Hz, 1 H), 8.97 (d, J=7.3 Hz, 1 H); ESI-MS m/z [M+H]⁺ 425.4.

EXAMPLE 68(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the titlecompound as a white solid (12.1 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.38 (d, J=6.8 Hz, 3 H), 4.89-4.99 (m, 1 H), 5.07 (s, 2 H),7.03-7.41 (m, 5 H), 7.95-8.05 (m, 2 H), 8.33-8.40 (m, 1 H), 8.77-8.84(m, 1 H); ESI-MS m/z [M+H]⁺ 393.4.

EXAMPLE 69(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-(difluoromethoxy)phenyl)ethanamine, HCl to give the titlecompound as a white solid (17.5 mg, 78%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.38 (d, J=6.8 Hz, 3 H), 3.93 (s, 3 H), 4.89-5.00 (m, 3 H),7.01-7.41 (m, 2 H), 7.11-7.16 (m, 1 H), 7.42-7.47 (m, 1 H), 7.67-7.72(m, 1 H), 7.99 (t, J=8.3 Hz, 1 H), 8.75 (d, J=7.8 Hz, 1 H); ESI-MS m/z[M+H]⁺ 405.4.

EXAMPLE 70(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give thetitle compound as a white solid (6.0 mg, 27%). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.40 (d, J=6.8 Hz, 3 H), 5.09 (s, 2 H), 5.13 (quin, J=7.1 Hz, 1H), 7.27 (d, J=8.8 Hz, 1 H), 7.36 (dd, J=10.5, 1.7 Hz, 1 H), 7.56 (t,J=8.5 Hz, 1 H), 7.92-7.99 (m, 1 H), 8.11 (td, J=7.6, 1.5 Hz, 1 H),8.21-8.28 (m, 2 H), 8.95 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 411.3.

EXAMPLE 71(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give thetitle compound as a white solid (7.8 mg, 33%). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.40 (d, J=6.8 Hz, 3 H), 5.09 (s, 2 H), 5.10-5.17 (m, 1 H), 7.27(d, J=9.8 Hz, 1 H), 7.36 (d, J=10.7 Hz, 1 H), 7.55 (t, J=8.5 Hz, 1 H),7.95-8.04 (m, 2 H), 8.36 (dd, J=8.5, 5.1 Hz, 1 H), 8.95 (d, J=7.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 429.2.

EXAMPLE 72(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethanamine, HCl to give thetitle compound as a white solid (11.8 mg, 49%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.37-1.42 (m, 3 H), 3.92 (s, 3 H), 4.99 (s, 2 H), 5.13(quin, J=7.2 Hz, 1 H), 7.26 (d, J=8.8 Hz, 1 H), 7.33-7.39 (m, 1 H), 7.44(d, J=8.3 Hz, 1 H), 7.56 (t, J=8.5 Hz, 1 H), 7.69 (dd, J=7.8, 1.0 Hz, 1H), 7.97-8.03 (m, 1 H), 8.90 (d, J=7.3 Hz, 1 H); ESI-MS m/z [M+H]⁺441.2.

EXAMPLE 73 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-phenethylacetamide

To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride(21 μL, 0.244 mmol). The mixture was allowed to stir at RT for 45 min,and was then added to a solution of 2-phenylethanamine (15 μL, 0.122mmol) and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reactionmixture was stirred at RT for 18 h. Purification by HPLC Method Aprovided the title compound as a white solid (11.1 mg, 30%). ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.73 (t, J=7.6 Hz, 2 H), 3.29-3.34 (m, 2 H), 5.00(s, 2 H), 7.20-7.33 (m, 5 H), 7.93-7.99 (m, 1 H), 8.12 (td, J=7.6, 1.5Hz, 1 H), 8.23-8.29 (m, 2 H), 8.41 (t, J=5.6 Hz, 1 H); ESI-MS m/z [M+H]⁺309.9.

EXAMPLE 74N-(4-chlorophenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

To a solution of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (25mg, 0.122 mmol) in DCM (406 μL) was added 1 drop DMF and oxalyl chloride(21 μL, 0.244 mmol). The mixture was stirred at RT for 45 min, thenadded to a solution of 2-(4-chlorophenyl)ethanamine (17 μL, 0.122 mmol)and triethylamine (19 μL, 0.134 mmol) in 400 μL DCM. The reactionmixture was stirred at RT for 18 h. Purification by flash silica gelchromatography, eluting with 0-70% EtOAc in heptanes provided the titlecompound as a white solid (5.2 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.73 (t, J=7.1 Hz, 2 H), 3.28-3.32 (m, 2 H), 4.99 (s, 2 H), 7.24-7.29(m, 2 H), 7.33-7.37 (m, 2 H), 7.93-8.00 (m, 1 H), 8.12 (td, J=7.6, 1.5Hz, 1 H), 8.23-8.29 (m, 2 H), 8.39 (t, J=5.6 Hz, 1 H); ESI-MS m/z [M,M+2]⁺ 342.9, 344.9.

EXAMPLE 75N-(3-chlorophenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 74 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and2-(3-chlorophenyl)ethanamine to give the title compound as a white solid(8.4 mg, 20%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.75 (t, J=7.1 Hz, 2 H),3.32-3.36 (m, 2 H), 4.99 (s, 2 H), 7.18-7.35 (m, 4 H), 7.96 (td, J=7.6,1.5 Hz, 1 H), 8.12 (td, J=7.6, 1.5 Hz, 1 H), 8.23-8.29 (m, 2 H), 8.41(t, J=5.6 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 342.9, 344.9.

EXAMPLE 76N-(4-methylphenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 73 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and2-(p-tolyl)ethanamine to give the title compound as a white solid (5.5mg, 14%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.26 (s, 3H), 2.68 (t, J=7.6Hz, 2H), 3.25-3.31 (m, 2H), 4.99 (s, 2H), 7.10 (s, 4H), 7.92-8.00 (m,1H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.23-8.29 (m, 2H), 8.37-8.42(m, 1H); ESI-MS m/z [M+H]⁺ 323.0.

EXAMPLE 77N-(4-hydroxyphenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 1 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and4-(2-aminoethyl)phenol to give the title compound as a white solid (26.7mg, 68%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.59-2.64 (m, 2 H), 3.22-3.25(m, 2 H), 4.99 (s, 2 H), 6.65-6.71 (m, 2 H), 7.00 (d, J=8.8 Hz, 2 H),7.93-7.99 (m, 1 H), 8.12 (td, J=7.8, 1.5 Hz, 1 H), 8.22-8.29 (m, 2 H),8.37 (t, J=5.6 Hz, 1 H), 9.15-9.19 (m, 1 H); ESI-MS m/z [M+H]⁺ 325.0.

EXAMPLE 78N-(4-methoxyphenethyl)-N-methyl-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 4 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and2-(4-methoxyphenyl)-N-methylethanamine to give the title compound as awhite solid (15.2 mg, 59%). Mixture of rotamers: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.66-2.73 (m, 1 H), 2.83-3.10 (m, 4 H), 2.90 (t, J=7.6Hz, 1 H), 3.41-3.46 (m, 1 H), 3.63 (t, J=7.3 Hz, 1 H), 3.70-3.76 (m, 3H), 5.11-5.34 (m, 2 H), 6.82-6.88 (m, 1 H), 6.89-6.94 (m, 1 H),7.12-7.16 (m, 1 H), 7.24-7.28 (m, 1 H), 7.92-8.01 (m, 1 H), 8.09-8.17(m, 1 H), 8.21-8.30 (m, 2 H); ESI-MS m/z [M+H]⁺ 353.9.

EXAMPLE 79 (S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(2-phenylpropyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-2-phenylpropan-1-amine to give the title compound as a white solid(12.5 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3 H),2.89 (sxt, J=7.1 Hz, 1 H), 3.24 (dd, J=7.1, 6.1 Hz, 2 H), 4.99 (s, 2 H),7.17-7.34 (m, 5 H), 7.92-7.99 (m, 1 H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1H), 8.22-8.29 (m, 2 H), 8.36 (t, J=5.9 Hz, 1 H); ESI-MS m/z [M+H]⁺323.0.

EXAMPLE 80(R)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(2-phenylpropyl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(R)-2-phenylpropan-1-amine to give the title compound as a white solid(13.1 mg, 56%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.20 (d, J=6.8 Hz, 3 H),2.86-2.93 (m, 1 H), 3.22-3.26 (m, 2 H), 4.99 (s, 2 H), 7.17-7.34 (m, 5H), 7.96 (td, J=7.6, 1.5 Hz, 1 H), 8.12 (ddd, J=8.4, 7.2, 1.5 Hz, 1 H),8.22-8.29 (m, 2 H), 8.36 (t, J=5.9 Hz, 1 H); ESI-MS m/z [M+H]⁺ 323.0.

EXAMPLE 81N-(2-chloro-4-methoxyphenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and2-(2-chloro-4-methoxyphenyl)ethanamine to give the title compound as awhite solid (16.6 mg, 61%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.78 (t,J=7.3 Hz, 2 H), 3.25-3.30 (m, 2 H), 3.31 (s, 2 H), 3.75 (s, 3 H), 4.99(s, 2 H), 6.87 (dd, J=8.5, 2.7 Hz, 1 H), 7.01 (d, J=2.9 Hz, 1 H),7.21-7.27 (m, 1 H), 7.93-8.00 (m, 1 H), 8.09-8.16 (m, 1 H), 8.22-8.30(m, 2 H), 8.42 (t, J=5.6 Hz, 1 H); ESI-MS m/z [M, M+2]⁺ 373.0, 374.9.

EXAMPLE 82(R)—N-(1-(4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(R)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as awhite solid (17.9 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d,J=6.8 Hz, 3 H), 2.53-2.72 (m, 2 H), 3.70-3.74 (m, 3 H), 3.91 (spt, J=6.8Hz, 1 H), 4.92-5.02 (m, 2 H), 4.97 (d, J=4.9 Hz, 2 H), 6.79-6.88 (m, 2H), 7.09-7.15 (m, 2 H), 7.92-8.00 (m, 1 H), 8.12 (ddd, J=8.4, 7.2, 1.5Hz, 1 H), 8.22-8.30 (m, 3 H); ESI-MS m/z [M+H]⁺ 354.0.

EXAMPLE 83(S)-N-(1-(4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-methoxyphenyl)propan-2-amine to give the title compound as awhite solid (14.1 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.03 (d,J=6.8 Hz, 3 H), 2.53-2.74 (m, 2 H), 3.70-3.74 (m, 3 H), 3.88-3.96 (m, 1H), 4.92-5.02 (m, 2 H), 6.81-6.88 (m, 2 H), 7.08-7.16 (m, 2 H), 7.96(ddd, J=8.1, 7.1, 1.5 Hz, 1 H), 8.12 (td, J=7.6, 1.5 Hz, 1 H), 8.22-8.30(m, 3 H); ESI-MS m/z [M+H]⁺ 353.9.

EXAMPLE 84(S)-N-(1-(4-chloro-2-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(4-chloro-2-methoxyphenyl)propan-2-amine to give the titlecompound as a white solid (19.7 mg, 70%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.03 (d, J=6.8 Hz, 3 H), 2.67 (d, J=6.8 Hz, 2 H), 3.78-3.82 (m, 3H), 3.97-4.07 (m, 1 H), 4.89-4.99 (m, 2 H), 6.92 (dd, J=7.8, 2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1 H), 7.14 (d, J=8.3 Hz, 1 H), 7.93-7.99 (m, 1H), 8.12 (td, J=7.6, 1.5 Hz, 1 H), 8.20 (d, J=7.8 Hz, 1 H), 8.22-8.28(m, 2 H); ESI-MS m/z [M, M+2]⁺ 386.9, 389.0.

EXAMPLE 85(S)-N-(1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide

The title compound was prepared in a manner similar to Example 2 using2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid and(S)-1-(2-chloro-4-methoxyphenyl)propan-2-amine, HCl to give the titlecompound as a tan solid (32.5 mg, 36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.07 (d, J=6.8 Hz, 3 H), 2.75-2.78 (m, 2 H), 3.75 (s, 3 H), 3.99-4.09(m, 1 H), 4.89-5.02 (m, 2 H), 6.86 (dd, J=8.5, 2.7 Hz, 1 H), 6.99 (d,J=2.4 Hz, 1 H), 7.22-7.27 (m, 1 H), 7.96-7.99 (m, 1 H), 8.12 (ddd,J=8.4, 7.2, 1.5 Hz, 1 H), 8.21-8.31 (m, 3 H); ESI-MS m/z [M, M+2]⁺386.9, 388.9.

EXAMPLE 86 (S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)propyl)acetamide

A mixture of 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (23 mg,0.11 mmol), (S)-1-(4-(trifluoromethoxy)phenyl)propan-1-aminehydrochloride (31.5 mg, 0.12 mmol), N-ethyl-N-isopropylpropan-2-amine(0.059 mL, 0.336 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (26 mg, 0.135 mmol) and 1H-benzo[d][1,2,3] triazol-1-ol(18 mg, 0.135 mmol) in DMF (1 mL) was stirred at room temperature for 3hours. The residue was diluted with MeOH then purified via HPLC Method Ato provide the title compound as an off-white solid (16 mg, 35%). ¹H NMR(500 MHz, chloroform-d) δ ppm 0.86-0.97 (m, 3 H) 1.79-1.91 (m, 2 H)4.87-4.96 (m, 1 H) 5.13 (s, 2 H) 6.20-6.28 (m, 1 H) 7.14-7.20 (m, 2 H)7.30-7.34 (m, 2 H) 7.80-7.89 (m, 1 H) 7.96-8.02 (m, 1 H) 8.17-8.26 (m, 1H) 8.36-8.40 (m, 1 H); ESI-MS m/z [M+H]⁺ 407.

EXAMPLE 87 (S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)propyl)acetamide

The title compound was prepared in a manner similar to Example 87 using(S)-1-(4-(trifluoromethyl)phenyl)propan-1-amine hydrochloride to givethe title compound as an off-white solid (19 mg, 56%). ¹H NMR (500 MHz,chloroform-d) δ ppm 0.92 (t, J=7.1 Hz, 3 H) 1.86 (t, J=7.3 Hz, 2 H) 4.95(d, J=7.3 Hz, 1 H) 5.13 (s, 2 H) 6.31 (d, J=7.8 Hz, 1 H) 7.40 (d, J=7.8Hz, 2 H) 7.59 (d, J=7.8 Hz, 2 H) 7.86 (d, J=8.3 Hz, 1 H) 8.00 (s, 1 H)8.21 (d, J=8.3 Hz, 1 H) 8.38 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]⁺ 391.

The compounds of the invention can be administered alone or in the formof a pharmaceutical composition. In practice, the compounds of theinvention are usually administered in the form of pharmaceuticalcompositions, that is, in admixture with at least one pharmaceuticallyacceptable excipient. The proportion and nature of any pharmaceuticallyacceptable excipient(s) are determined by the properties of the selectedcompound of the invention, the chosen route of administration, andstandard pharmaceutical practice.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising: a compound of invention and at least onepharmaceutically acceptable excipient.

In effecting treatment of a patient in need of such treatment, acompound of the invention can be administered in any form and routewhich makes the compound bioavailable. The compounds of the inventioncan be administered by a variety of routes, including orally, inparticularly by tablets and capsules. The compounds of the invention canbe administered by parenteral routes, more particularly by inhalation,subcutaneously, intramuscularly, intravenously, intraarterially,transdermally, intranasally, rectally, vaginally, occularly, topically,sublingually, and buccally, intraperitoneally, intraadiposally,intrathecally and via local delivery for example by catheter or stent.

One skilled in the art can readily select the proper form and route ofadministration depending upon the particular characteristics of thecompound selected, the disorder or condition to be treated, the stage ofthe disorder or condition, and other relevant circumstances. Thepharmaceutical compositions of the invention may be administered to thepatient, for example, in the form of tablets, capsules, cachets, papers,lozenges, wafers, elixirs, ointments, transdermal patches, aerosols,inhalants, suppositories, solutions, and suspensions.

The pharmaceutical compositions of the present invention are prepared ina manner well known in the pharmaceutical art and include at least oneof the compounds of the invention as the active ingredient. The amountof a compound of the invention may be varied depending upon itsparticular form and may conveniently be between 1% to about 50% of theweight of the unit dose form. The term “pharmaceutically acceptableexcipient” refers to those typically used in preparing pharmaceuticalcompositions and should be pharmaceutically pure and non-toxic in theamounts used. They generally are a solid, semi-solid, or liquid materialwhich in the aggregate can serve as a vehicle or medium for the activeingredient. Some examples of pharmaceutically acceptable excipients arefound in Remington's Pharmaceutical Sciences and the Handbook ofPharmaceutical Excipients and include diluents, vehicles, carriers,ointment bases, binders, disintegrates, lubricants, glidants, sweeteningagents, flavoring agents, gel bases, sustained release matrices,stabilizing agents, preservatives, solvents, suspending agents, buffers,emulsifiers, dyes, propellants, coating agents, and others.

The present pharmaceutical compositions are preferably formulated in aunit dose form, each dose typically containing from about 0.5 mg toabout 100 mg of a compounds of the invention. The term “unit dose form”refers to a physically discrete unit containing a predetermined quantityof active ingredient, in association with a suitable pharmaceuticalexcipient, by which one or more is used throughout the dosing regimen toproduce the desired therapeutic effect. One or more “unit dose form” maybe taken to affect the treatment dosage, typically on a daily schedule.

In one particular variation, the composition is a pharmaceuticalcomposition adapted for oral administration, such as a tablet or acapsule or a liquid formulation, for example, a solution or suspension,adapted for oral administration. In still another particular variation,the pharmaceutical composition is a liquid formulation adapted forparenteral administration.

In another embodiment, the invention provides a method of treating adisease, disorder or condition associated with GPR139, comprising:administering to a patient in need thereof an effective amount of acompound of the invention. In another embodiment, a compound of theinvention is provided for use as a medicament. The invention alsoprovides the use of a compound of the invention, including the use forthe manufacture of a medicament, to treat a disease, disorder orcondition associated with GPR139 described herein. The compounds of theinvention are GPR139 agonists for treating a variety of subjects (e.g.,humans, non-human mammals and non-mammals).

As used herein terms “condition,” “disorder,” and “disease” relate toany unhealthy or abnormal state. The compounds of the invention areGPR139 agonists and may be useful for treating a variety of conditions.The term “disease, disorder or condition associated with GPR139”includes conditions, disorders, and diseases in which an agonist ofGPR139 may provide a therapeutic benefit, such as CNS disorders,disorders of the pancreas, such as pancreatitis, phenylketonuria, andpituitary disorders.

The term “disease, disorder or condition associated with GPR139”includes specifically, but is not limited to, CNS disorders such asschizophrenia, autism spectrum disorder, sleep disorders, depression,bipolar disorder, cognitive impairment, including mild cognitiveimpairment, Alzheimer's Disease, disorders affecting short term memory,disorders affecting long term memory, attention deficit hyperactivitydisorder, post-traumatic stress disorder, substance abuse, drugaddiction, eating disorders, obsessive compulsive disorder, anxietydisorders, including generalized anxiety disorder and social anxietydisorder, pain, fibromyalgia and other disorders mentioned herein, amongothers.

Schizophrenia is a chronic, severe, and disabling disordercharacterized, in part, by negative symptoms, such as blunted affect,deficits in social functioning, anhedonia, avolition and poverty ofspeech, and by cognitive impairment associated with schizophrenia(CIAS), such as impairment in attention, working memory, executivefunction and social cognition. Autism spectrum disorder is a group ofdevelopmental disabilities that can cause significant social,communication and behavioral challenges (repetitive and stereotypedbehavior). Because of the pro-social effects expected from GPR139agonists, the present compounds may treat schizophrenia and autismspectrum disorder.

In particular, the term “disease, disorder or condition associated withGPR139” includes schizophrenia.

In particular, the term “disease, disorder or condition associated withGPR139” includes autism spectrum disorder.

In particular, the term “disease, disorder or condition associated withGPR139” includes addiction. Examples include addiction to nicotine,alcohol, and/or cocaine.

In particular, the term “disease, disorder or condition associated withGPR139” includes attention deficit hyperactivity disorder.

In particular, the term “disease, disorder or condition associated withGPR139” includes bipolar disorder.

In particular, the term “disease, disorder or condition associated withGPR139” includes depression, such as major depressive disorder.

The terms “treat,” “treatment,” and “treating” include improvement ofthe conditions described herein. The terms “treat,” “treatment,” and“treating” include all processes providing slowing, interrupting,arresting, controlling, or stopping of the state or progression of theconditions described herein, but does not necessarily indicate a totalelimination of all symptoms or a cure of the condition. The terms“treat,” “treatment,” and “treating” are intended to include therapeutictreatment of such disorders. The terms “treat,” “treatment,” and“treating” are intended to include prophylactic treatment of suchdisorders.

As used herein the terms “patient” and “subject” includes humans andnon-human animals, for example, mammals, such as mice, rats, guineapigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. Theterm also includes birds, fish, reptiles, amphibians, and the like. Itis understood that a more particular patient is a human. Also, moreparticular patients and subjects are non-human mammals, such as mice,rats, and dogs.

As used herein, the term “effective amount” refers to the amount ofcompound of the invention which treats, upon single or multiple doseadministration, a patient suffering from the mentioned condition. Aneffective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount, the dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of patient; its size, age, and general health; thespecific condition, disorder, or disease involved; the degree of orinvolvement or the severity of the condition, disorder, or disease, theresponse of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances. An effective amount of the present invention, thetreatment dosage, is expected to range from 1 mg to 100 mg. Specificamounts can be determined by the skilled person. Although these dosagesare based on an average human subject having a mass of about 60 kg toabout 70 kg, the physician will be able to determine the appropriatedose for a patient having a mass that falls outside of this weightrange.

The compounds of the invention may be combined with one or more otherpharmacologically active compounds or therapies for the treatment of oneor more disorders, diseases or conditions for which GPR139 is indicatedmay be administered simultaneously, sequentially or separately incombination with one or more compounds or therapies for treating aparticular disease, disorder or condition associated with GPR139.

For example, in the treatment of schizophrenia the compounds of theinvention may be administered in combination with sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones,imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, benzodiazepines,barbiturates, mGlu2/3 agonists, 5HT-2 antagonists, PDE10 antagonists,GlyT1 inhibitors, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amisulpride, amitriptyline, amobarbital,amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam,bupropion, busprione, butabarbital, butalbital, capuride, carbocloral,chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone,clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine,cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone,divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol,etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine,flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,haloperidol, hydroxyzine, imipramine, lithium, lorazopam, lormetazepam,maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazopam,nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine,pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital,prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine,reclazepam, risperidone, roletamide, secobarbital, sertraline,suproclone, temazopam, thioridazine, thiothixene, tracazolate,kanylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos,trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine,zaleplon, ziprasidone, zolazepam, zolpidem, and the like.

Also for example, in the treatment of depression the compounds of theinvention may be administered in combination with an anti-depressant oranti-anxiety agent, including norepinephrine reuptake inhibitors(including tertiary amine tricyclics and secondary amine tricyclics),selective serotonin reuptake inhibitors (SSRIs), monoamine oxidaseinhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs),serotonin and noradrenaline reuptake inhibitors (SNR1s), corticotropinreleasing factor (CRF) antagonists, adrenoreceptor antagonists,neurokinin-1 receptor antagonists, atypical anti-depressants,benzodiazopines, 5-HTA agonists or antagonists, especially 5-HTA partialagonists, and corticotropin releasing factor (CRF) antagonists. Specificagents include: amitriptyline, clomipramine, doxepin, imipramine andtrimipramine; amoxapine, desipramine, maprotiline, nortriptyline andprotriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline;isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide,venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazopam,chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and the like.

In yet another example, in the treatment of Alzheimer's disease or mildcognitive impairment the compounds of the invention may be administeredin combination with anti-Alzheimer's agents, beta-secretase inhibitors,gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID'sincluding ibuprofen, vitamin E, anti-amyloid antibodies, also sedatives,hypnotics, anxiolytics, antipsychotics, antianxiety agents, andtranquilizers, and such other medications as are used in the treatmentof Alzheimer's disease or mild cognitive impairment.

The activity of compounds as GPR139 agonists may be determined by avariety of methods, including in vitro and in vivo methods.

EXAMPLE A GPR139 Competition Binding

This membrane based assay measures the ability of compounds tocompetitively bind GPR139 in stably transfected CHO-TRex membranes.CHO-TRex (Life Technologies) cells were stably expressed with humanGPR139 receptor, whose expression is controlled by a tetracyclineinducible element. The cells were cultured in medium containing F12K,10% Tetracycline free FBS, 1% Penn/Strep, 200 μg/mL Hygromycin. GPR139receptor expression was induced for 18 hrs with 1 μg/mL doxycycline(Sigma D9891) in growth media. After addition of doxycycline, cells wereharvested in PBS and pelleted by centrifugation for 5 minutes at 200×G.Liquid was aspirated off and cells were resuspended in ice cold Lysisbuffer (20 mM HEPES/5 mM EDTA pH 7.4/1× Roche protease inhibitor).Samples were vortexed until homogenous and then placed on ice andhomogenized using Dounce homogenizer on 50% power 3 separate times for10 strokes each time. Lysate was centrifuged at 4° C. for 10 minutes ina tabletop Sorvall at 2000×G and supernatant was recovered andcentrifuged in a Sorvall Ultracentrifuge at 35,000 rpm for 30 minutes at4° C. The supernatant was discarded and the remaining pellet resuspendedin Lysis buffer (20 mM HEPES/0.1 mM EGTA/Roche protease inhibitor).Membrane protein concentration was determined using ThermoFisher BCAquantification kit and aliquoted into microtubes. Tubes were snap frozenin LN2 and stored at −80° C.

Membranes were removed from −80° C., thawed and diluted in coldradioligand assay buffer (20 mM HEPES pH 7.4/5 mM MgCl₂/1 mM CaCl₂/Rocheprotease inhibitor). Compounds suspended in DMSO were diluted in 1 nM(S)-N-(1-(2-[³H]-4-methoxyphenyl)propan-2-yl)-2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetamide,readily prepared from(S)-N-(1-(2-chloro-4-hydroxyphenyl)propan-2-yl)-2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetamide(20 mM HEPES pH 7.4/5 mM MgCl₂/1 mM CaCl₂/Roche protease inhibitorfresh/(S)-N-(1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-(2,3-dimethyl-7-oxothieno[2,3-d]pyridazin-6(7H)-yl)acetamide)in a 0.3 mL 96 well polypropylene assay plate (Fisher Scientific).Membranes (10 μg) were added to the assay plate, spun for 30 seconds at300 rpm in a tabletop Eppendorf centrifuge, and then incubated at roomtemperature for 20 minutes. Filtermat A (Perkin Elmer No. 1450-421) ispre-soaked in 0.5% PEI (Sigma P3143) for 3 hours and dried at roomtemperature overnight. The contents of the assay plate were transferredto Filtermat A (Perkin Elmer No. 1450-421) using Tomtec harvester andwashed 5 times with cold wash buffer (Tris-HCl pH 7.5). Filtermats weredried using a microwave oven and placed in sample bags (Perkin Elmer No.1450-432) with scintillator sheets (Perkin Elmer No. 1450-411).Scintillator sheets were melted to filtermats using a heat block set to65° C., placed in MicroBeta cartridges and read using the MicroBetascintillation counter. Binding Ki curves were generated with afour-parameter logistic equation using GraphPad Prism 6. Table Aprovides results for the exemplified compounds in Example A.

TABLE A GPR139 Inhibition (Ki (nM)) for Example (Ex) Compounds EX Ki 11621 2 119 3 48 4 NT 5 467 6 NT 7 1362 8 228 9 63 10 1148 11 953 12 264413 148 14 182 15 909 16 708 17 3601 18 58 19 189 20 551 21 173 22 110 23842 24 72 25 526 26 26 27 190 28 179 29 915 30 791 31 4188 32 459 334850 34 347 35 1517 36 437 37 1466 38 619 39 92 40 533 41 10 42 179 43435 44 2531 45 85 46 1562 47 NT 48 NT 49 NT 50 NT 51 NT 52 39 53 171 5477 55 42 56 218 57 128 58 33 59 375 60 115 61 26 62 240 63 352 64 106 65152 66 677 67 11 68 282 69 120 70 120 71 93 72 33 73 NT 74 1236 75 168876 5553 77 NT 78 NT 79 NT 80 4448 81 117 82 NT 83 802 84 NT 85 NT 86 18387 214

EXAMPLE B Activation of Calcium Signaling of GPR139 In Vitro Assay

This cell based assay measures the ability of compounds to activateGPR139 in stably transfected CHO-TRex cells. CHO-TRex (LifeTechnologies) cells were stably expressed with human GPR139 receptor,whose expression is controlled by a tetracycline inducible element. Thecells were cultured in medium containing F12K, 10% Tetracycline freeFBS, 1% Penn/Strep, 200 μg/mL Hygromycin. GPR139 receptor expression wasinduced for 18 hours with 1 μg/mL doxycycline (Sigma D9891) in growthmedia. After addition of doxycycline, cells were plated at a density of30,000 cells per well in black 96 well clear bottom plates (Costar) andplaced in an incubator (37°, 5% CO₂) for 18 hours prior to calciumassays.

Culture media was removed from cells and 200 μL of Calcium 5 dye (30 mL1×HBSS/20 mM Hepes pH 7.4, 1 mM probenecid/vial Molecular DevicesCalcium 5 dye) was added to cells and incubated for 40 min at 37° C. and5% CO₂. Compounds suspended in DMSO were diluted in 1×HBSS 20 mM Hepesbuffer pH7.4. After incubation, cells were incubated for 15 min at roomtemperature. Compounds were added to cells using the FLIPR Tetra(Molecular Devices) and fluorescence measured continuously for 1 minute.EC₅₀ curves were generated with a four-parameter logistic equation usingGraphPad Prism 6. The specific compounds of this invention had an EC₅₀value of less than about 100 micromolar. Table B provides results forthe exemplified compounds in Example B.

EXAMPLE C Balb/c Social Interaction Test

Young Balb/c mice show a natural deficit in sociable behaviors when putin a laboratory situation exposing them to an unfamiliar or “stimulus”mouse of a different strain. Social withdrawal or flattening of socialbehaviors is a feature of several disorders including schizophrenia andautism. Therefore this natural deficit seen in BalbC mice may be used(as a pre-clinical, non-pharmacologically induced model) to testpotential pro-social effects of compounds intended to be used to treatthe social aspects of disorders.

Methods: Balb/c male mice (4-5 weeks old) are acclimatized to the studyroom prior to start of the session (1 hour). Animals (n=15/group) arethen dosed with vehicle (10 mL/mg) or test compound. After dosing, miceare returned to their home cage for the appropriate pre-treatment time.Following this, mice are placed individually into the center area of theSocial Interaction (SI) box and allowed to explore freely for 5 minutesto habituate. They are then removed and the age-matched stimulus C57BL/6mouse is placed in an enclosed stimulus Perspex cylinder in either thefar left area or the far right area of the SI box. As soon as thestimulus C57BL/6 mouse is placed in the SI box the test mouse will beplaced back into the center chamber and allowed to run freely around fora further 5 minutes. The activity of the test mouse is automaticallymonitored via Panlab's SMART tracking software throughout. The scoring(blinded to treatment) of sniffing interactions with either the stimuluscylinder or empty cylinder is manually recorded. Sniffing index (timesniffing stimulus cylinder-empty cylinder/time spent sniffing stimuluscylinder+empty cylinder) is used as the key measure of sociablebehavior. Table C provides results for the exemplified compounds inExample C.

TABLE B GPR139 Activation of Calcium Signaling (EC50 (nM)) for Example(Ex) Compounds EX EC₅₀ 1 54 2 22 3 24 4 24 5 9 6 7 7 NT 8 33 9 15 10 2711 24 12 67 13 91 14 11 15 16 16 9 17 27 18 10 19 13 20 16 21 17 22 7 2313 24 9 25 8 26 16 27 7 28 10 29 19 30 30 31 39 32 16 33 41 34 7 35 4236 19 37 70 38 26 39 6 40 9 41 7 42 37 43 45 44 15 45 36 46 11 47 14 481514 49 22 50 52 51 16 52 24 53 33 54 55 38 56 37 57 43 58 22 59 51 6018 61 15 62 25 63 50 64 13 65 21 66 18 67 20 68 10 69 17 70 29 71 49 7249 73 1303 74 21 75 65 76 30 77 NT 78 80 79 NT 80 288 81 117 82 NT 83802 84 NT 85 NT 86 50 87 31

TABLE C Sniffing Index for Balb/c Social Interaction Test Test CompoundDose Sniffing Index SEM Vehicle 10 mL/mg 0.3449 0.08677 Example 2 0.03mg/kg 0.5363 0.07839 0.3 mg/kg 0.6023 0.06546 3.0 mg/kg 0.6116 0.05989Vehicle 10 mL/mg 0.1299 0.06292 Example 3 0.01 mg/kg 0.2790 0.08543 0.03mg/kg 0.5185 0.07124 0.1 mg/kg 0.4957 0.05945 Vehicle 10 mL/mg 0.18170.1041 Example 5 0.3 mg/kg 0.4715 0.05589 3 mg/kg 0.5756 0.1085 30 mg/kg0.6701 0.04847 Vehicle 10 mL/mg 0.2595 0.1788 Example 13 0.03 mg/kg0.6017 0.05771 0.3 mg/kg 0.7280 0.04914 3 mg/kg 0.2621 0.1557 Vehicle 10mL/mg 0.3016 0.1127 Example 18 0.03 mg/kg 0.4742 0.06643 0.1 mg/kg0.5100 0.1090 0.3 mg/kg 0.6531 0.05789 30 mg/kg 0.6481 0.07488

EXAMPLE D Poly(I:C) Social Interaction Test

Mice are social animals. Disturbance of social approach and avoidanceare disabling symptoms of social phobia, social anxiety, autism,schizophrenia, and depression which may be modeled in mice. ThePoly(I:C) Social Interaction Test is based on the free choice by asubject mouse to spend time interacting with an unfamiliar mouse orempty cylinder. Offspring from GD17 Poly(I:C) treated mothers show adeficit in social interaction in this test as compared to offspring fromvehicle injected mothers. The reversal of this deficit may be used totest the potential pro-social effects of compounds intended to be usedto treat the social aspects of disorders.

Methods: C57BL/6 mice (˜14-16 weeks old) of Poly(I:C) or vehicle treatedmothers are acclimatized to the study room prior to start of the session(1 hour). Animals are then dosed with vehicle (10 mL/kg) or testcompound (n=12/group). After dosing, mice are returned to their homecage for the appropriate compound pre-treatment time (acute orpre-treated for 13 days before standard acute test was performed).Following this, mice are placed individually into the centre area of theSI box and allowed to explore freely for 2 minutes to habituate. Theage-matched stimulus C57BL/6 mouse is then placed in an enclosedstimulus Perspex cylinder in either the far left area or the far rightarea of the SI box. The test mouse may then explore freely for a further5 minutes. The activity of the test mouse is automatically monitored viaPanlab's SMART tracking software throughout. The scoring (blinded totreatment) of sniffing interactions with either the stimulus cylinder orempty cylinder is manually recorded. Sniffing index (time sniffingstimulus cylinder-empty cylinder/time spent sniffing stimuluscylinder+empty cylinder) is used as the key measure of sociablebehavior.

TABLE D Sniffing Index for Poly(I:C) Social Interaction Test TestOffspring Sniffing Compound Tested Dose Index SEM Vehicle Vehicle 10mL/kg 0.6940 0.03800 Vehicle Poly(I:C) 10 mL/kg 0.3347 0.09289 Example 2Poly(I:C) 0.01 mg/kg 0.3906 0.07594 Example 2 Poly(I:C) 0.1 mg/kg 0.61830.04157 Example 2 Poly(I:C) 1.0 mg/kg 0.5794 0.04119 Vehicle* Vehicle 10mL/kg 0.7085 0.03369 Vehicle* Poly(I:C) 10 mL/kg 0.3321 0.08627Vehicle*/Example 2 Poly(I:C) 0.01 mg/kg 0.6308 0.04213 Example2*/Example 2 Poly(I:C) 0.1 mg/kg 0.5910 0.06561 Vehicle Vehicle 10 mL/kg0.6002 0.05238 Example 5 Vehicle 30 mg/kg 0.6104 0.04409 VehiclePoly(I:C) 10 mL/kg 0.4103 0.06206 Example 5 Poly(I:C) 0.3 mg/kg 0.54100.02821 Example 5 Poly(I:C) 3 mg/kg 0.5897 0.05552 Example 5 Poly(I:C)30 mg/kg 0.6232 0.06749 Vehicle Vehicle 10 mL/kg 0.6873 0.04139 VehiclePoly(I:C) 10 mL/kg 0.3263 0.05871 Example 18 Poly(I:C) 0.3 mg/kg 0.52000.03283 Example 18 Poly(I:C) 3 mg/kg 0.5276 0.04350 Example 18 Poly(I:C)30 mg/kg 0.5586 0.04619 *dosed for 13 days before test was performed

EXAMPLE E cFos Staining

To demonstrate target engagement in vivo, c-Fos immunoreactivity wasmeasured in the dorsal medial habenula following oral dosing. SinceGPR139 is Gq-coupled, dosing with present compounds induced c-Fosexpression, a common signaling mechanism in activated neurons (Cohen &Greenberg, Ann. Rev. Cell Dev. Biol. (2008)).

Methods: After dosing C57/B16 mice for various time courses their brainswere prepared for immunohistochemistry. One hour after the final oraldose is administered C57/B16 mice are perfused with 100 mL 4%paraformaldehyde in PBS. Brains are extracted and placed in 4%paraformaldehyde for 3 hours, changed into 20% sucrose/PBS solution toavoid freezing artifacts, and frozen with dry ice. Frozen brain sectionsare obtained with sliding microtome at 20 um and washed in PBS (2 timesfor 10 minutes each). Endogenous peroxidase enzyme is blocked with 0.3%H₂O₂ solution in water for 10 minutes. Sections are rinsed in PBS (3times for 10 minutes each) and incubated in primary antibody againstcFos (Santa Cruz SC-42) at a dilution of 1:10,000 at 4° C. overnight inPBS+0.3% triton and 1% bovine serum albumin. Sections are subsequentlyrinsed in PBS (3 times for 10 minutes each) and incubated in secondaryantibody: goat against rabbit-biotinylated antibody, at a dilution of1:200 for 1 hour at room temperature in PBS+0.3% triton and 1% bovineserum albumin. Sections are rinsed in PBS (3 times for 10 minutes each)and incubated in ABC mix in PBS: ABC Elite Kit from Vector (PK-1000) for1 hour at room temperature. Next, the sections are rinsed in PBS (3times for 10 minutes each) and then in 0.1 M sodium acetate (3 times for10 minutes each). Reaction is visualized with standard diaminobenzydineprocedures: 50 mL of 0.1M sodium acetate containing 20 mg ammoniumchloride, 20 mg, diaminobenzydine, 80 mg glucose and 10 mL of glucoseoxidase. React for 10 minutes then the reaction is stopped with PBSrinses (3 times for 10 minutes each). cFos cells are then counted. ThecFos cell count is provided in Tables E.1, E.2, E.2, and E.4.

TABLE E.1 cFos cell count in desensitization experiment with Example 2vehicle vehicle 0.1 mg/kg 0.1 mg/kg 0.1 mg/kg 1 d 10 d 1 d 5 d 10 dNumber of mice 5 5 5 5 5 Mean 352 450 1486 1928 1684 Std. Deviation218.6 192.2 789.7 833.6 457.4 SEM 97.74 85.97 353.2 372.8 204.5

TABLE E.2 cFos cell count in dose response curve experiment with Example2 vehicle 0.01 mg/kg 0.03 mg/kg 0.1 mg/kg 0.3 mg/kg 1 mg/kg Number ofmice 5 5 4 4 4 5 Mean 267 1376 986.3 1381 1408 1368 Std. Deviation 169.8566.3 224.3 297.7 229.1 507.8 SEM 75.94 253.3 112.2 148.8 114.6 227.1Sum 1335 6880 3945 5525 5630 6840

TABLE E.3 cFos cell count in time course experiment with Example 2 0.1mg/kg 0.3 mg/kg 3 mg/kg 0.3 mg/kg 0.3 mg/kg vehicle 1 hr 1 hr 1 hr 2 hr4 hr Number of mice 3 3 3 3 3 3 Mean 413.7 787.7 1343 2365 1400 2170Std. Deviation 82.1 71.14 509.7 450.1 151 333.9 SEM 47.4 41.07 294.3259.9 87.18 192.8

TABLE E.4 cFos cell count in dose-response and time course experimentwith Example 3 0.03 mg/kg 0.1 mg/kg 0.3 mg/kg 3 mg/kg 0.3 mg/kg 0.3mg/kg vehicle 1 hr 1 hr 1 hr 1 hr 2 hr 4 hr Number of mice 3 3 3 3 3 3 2Mean 470 1628 2243 2458 2023 2777 865 Std. Deviation 78.58 272.8 712.9167.7 383.7 1249 134.4 SEM 45.37 157.5 411.6 96.8 221.5 720.9 95

What is claimed is:
 1. A method for agonizing GPR139 in a subject, themethod comprising administering to the subject a compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein m is selectedfrom 0, 1, and 2; n is selected from 0, 1, and 2; each R₁ isindependently selected from the group consisting of cyano, halo,hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, andtrifluoromethoxy; each R₄ is independently selected from the groupconsisting of cyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy,trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy;and R₅ is selected from the group consisting of hydrogen,trifluoromethyl, and C₁₋₄ alkyl, provided: (a) if R₅ is hydrogen,methyl, n-propyl, i-propyl, or i-butyl, then m and n are not both 0; (b)if R₅ is hydrogen, m is 0, and n is 1, then R₄ is not chloro, methoxy,3-trifluoromethyl, 4-trifluoromethyl, 4-methyl, 4-fluoro,2-difluoromethoxy, 3-difluoromethoxy, 2-trifluoromethoxy,4-trifluoromethoxy, or 2-(i-butoxy); (c) if R₅ is methyl, m is 0, and nis 1, then R₄ is not chloro, 2-fluoro, 4-fluoro, 2-bromo, 4-ethyl,2-methyl, 4-(i-propyl), 4-(i-butyl), or 3-trifluoromethyl; (d) if R₅ isethyl, m is 0, and n is 1, then R₄ is not 3-chloro, 4-chloro, 4-bromo,4-methyl, 4-methoxy, or 2-difluoromethoxy; (e) if R₅ is n-propyl, m is0, and n is 1, then R₄ is not 3-trifluoromethyl; (f) if R₅ is i-propyl,m is 0, and n is 1, then R₄ is not 4-fluoro or 4-methoxy; (g) if R₅ isi-butyl, m is 0, and n is 1, then R₄ is not 3-trifluoromethyl; (h) if R₅is hydrogen, m is 0, and n is 2, then R₄ is not 2,6-difluoro,2,4-dichloro, 3,5-dimethoxy, 3,4-dimethoxy, 4-methoxy-3-difluoromethoxy,4-fluoro-2-trifluoromethyl, or 5-bromo-2-difluormethoxy; and (i) if R₅is methyl, m is 0, and n is 2, then R₄ is not 3,4-dimethyl,3,4-dichloro, 2,4-dichloro, 3-fluoro-4-methoxy, 3-bromo-4-methoxy,3-methoxy-4-isopropyloxy, or 3-methoxy-4-isobutyloxy.
 2. The methodaccording to claim 1, wherein the compound is substantiallyenantiomerically pure and has a structure represented by formula 2A,

wherein R₅ is selected from the group consisting of trifluoromethyl andC₁₋₄ alkyl.
 3. The method according to claim 1, wherein m is
 0. 4. Themethod according to claim 1, wherein R₅ is C₁₋₄ alkyl.
 5. The methodaccording to claim 1, wherein R₅ is selected from the group consistingof methyl, ethyl, and isopropyl.
 6. The method according to claim 1,wherein R₅ is methyl.
 7. The method according to claim 1, wherein n is 1and R₄ is trifluoromethoxy.
 8. The method according to claim 1, whereinm is
 1. 9. The method according to claim 1, wherein m is
 2. 10. Themethod according to claim 1, wherein the compound is selected from thegroup of compounds consisting of: 2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide; N-(1-(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; 2-(4-oxobenzo[d] [1,2,3 ]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-ethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2,4-dimethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; 2-(5 -fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide; 2-(5-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; 2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide; N-(1-(4-methoxyphenyl)ethyl)-2-(7-methyl-4-oxobenzo[d] [1,2,3 ]triazin-3(4H)-yl)acetamide; 2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1 -p-tolylethyl)acetamide; 2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide; 2-(5-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; N-(1 -(4-methoxyphenyl)ethyl)-2-(5-methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide; 2-(6,8-dimethyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide; N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3 (4H)-yl)acetamide; 2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1 -(p-tolyl)ethyl)acetami de; N-(1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; N-(1-(2-bromo-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; N-(1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)propanamide; N-(1-(2,4-dimethylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;and a pharmaceutically acceptable salt of any one of the above-mentionedcompounds.
 11. The method according to claim 1, wherein the compound isselected from the group of compounds consisting of:(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(R)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-l)acetamide;(S)-N-(1-(4-ethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2,4-dimethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(6, 8-dimethyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3 (4H)-yl)acetamide;(S)-2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(p-tolyl)ethyl)acetami de; (S)-N-(1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide;(S)-N-(1-(2-bromo-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide; (S)-N-((S)-1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)propanamide; (R)-N-((S)- 1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)propanamide; (S)-N-(1-(2,4-dimethylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide; (S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1 -(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;and a pharmaceutically acceptable salt of any one of the above-mentionedcompounds.
 12. The method according to claim 1, wherein the compound isselected from the group of compounds consisting of: (S)-2-(4-oxob enzo[d][1,2,3 ]tri azin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)propyl)acetamide;(S)-2-(4-oxobenzo [d][1,2,3 ]tri azin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)propyl)acetamide; and apharmaceutically acceptable salt of any one of the above-mentionedcompounds.
 13. The method according to claim 1, wherein the compound is(S)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide or a pharmaceuticallyacceptable salt thereof.
 14. The method according to claim 1, whereinthe compound is(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamideor a pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 1, wherein the compound is(S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamideor a pharmaceutically acceptable salt thereof.
 16. The method accordingto claim 1, wherein the compound is(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamideor a pharmaceutically acceptable salt thereof.
 17. A method foragonizing GPR139 in a subject, the method comprising administering tothe subject a compound of formula 1,

or a pharmaceutically acceptable salt thereof, wherein: m is selectedfrom 0, 1, and 2; n is selected from 0, 1, and 2; each R₁ isindependently selected from the group consisting of cyano, halo,hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, andtrifluoromethoxy; R₂ is selected from the group consisting of hydrogenand C₁₋₄ alkyl; R₃ is selected from the group consisting of hydrogen andmethyl; each R₄ is independently selected from the group consisting ofcyano, halo, hydroxy, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,fluoromethoxy, difluoromethoxy, and trifluoromethoxy; G is selected fromthe group consisting of —CHR₅—, —CHR₅—CH₂—, and —CH₂—CHR₅—; and R₅ isselected from the group consisting of hydrogen, trifluoromethyl, andC₁₋₄ alkyl.
 18. The method according to claim 17, wherein G is —CHR₅—.19. The method according to claim 17, wherein R₅ is selected from thegroup consisting of methyl, ethyl, and isopropyl.
 20. The methodaccording to claim 17, wherein R₅ is methyl.
 21. The method according toclaim 17, wherein the compound is substantially enantiomerically pureand has a structure represented by formula 1A,

wherein R₅ is selected from the group consisting of trifluoromethyl andC₁₋₄ alkyl.
 22. The method according to claim 17, wherein R₂ ishydrogen.
 23. The method according to claim 17, wherein R₃ is hydrogen.24. The method according to claim 17, wherein m is
 0. 25. The methodaccording to claim 17, wherein m is
 1. 26. The method according to claim25, wherein R₁ is selected from the group consisting of halo, C₁₋₄alkyl, C₁₋₄ alkoxy, trifluoromethyl, and trifluoromethoxy.
 27. Themethod according to claim 25, wherein R₁ is C₁₋₄ alkoxy.
 28. The methodaccording to claim 17, wherein m is
 2. 29. The method according to claim17, wherein n is 1 and R₄ is selected from the group consisting of halo,C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, fluoromethoxy,difluoromethoxy, and trifluoromethoxy.
 30. The method according to claim17, wherein n is 1 and R₄ is selected from the group consisting of C₁₋₄alkyl and trifluoromethoxy.
 31. The method according to claim 17,wherein the compound is selected from the group of compounds consistingof: 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-phenylethyl)acetamide;2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-chlorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-o-tolylethyl)acetamide;N-(1-(4-ethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2,4-dimethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;N-(1-(4-methoxyphenyl)ethyl)-2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(6,8-dimethyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide; N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin-3 (4H)-yl)acetamide; 2-(8 -fluoro-6-methyl-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1 -(p-tolyl)ethyl)acetami de; N-(1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; N-(1-(2-bromo-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; N-(1 -(4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide; N-(1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)propanamide; N-(1-(2,4-dimethylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide; 2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1 -(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(6-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide; 2-(5-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;and a pharmaceutically acceptable salt of any one of the above-mentionedcompounds.
 32. The method according to claim 17, wherein the compound isselected from the group of compounds consisting of:(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-phenylethyl)acetamide;(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(R)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-chlorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-o-tolylethyl)acetamide;(S)-N-(1-(4-ethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2,4-dimethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;(S)-2-(6-methyl-4-oxobenzo[d] [1,2,3 ]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide; (S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;(S)-2-(7-methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(7-methyl-4-oxobenzo[d] [1,2,3]triazin-3 (4H)-yl)acetamide; (S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide; (S)-2-(5 -methoxy-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide; (S)-N-(1-(4-methoxyphenyl)ethyl)-2-(5 -methyl-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide; (S)-2-(6, 8-dimethyl-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;(S)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1-p -tolylethyl)acetamide;(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3]triazin -3 (4H)-yl)acetamide;(S)-2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-(p -tolyl)ethyl)acetamide; (S)-N-(1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetamide;(S)-N-(1-(2-bromo-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N4S)-1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-y1)propanamide;(R)-N4S)-1-(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-y1)propanamide;(S)-N-(1-(2,4-dimethylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(2-phenylpropyl)acetamide;(R)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(2-phenylpropyl)acetamide;(R)-N-(1-(4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-chloro-2-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-phenethylacetamide;N-(4-chlorophenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(3-chlorophenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(4-methylphenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(4-hydroxyphenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;N-(4-methoxyphenethyl)-N-methyl-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(2-phenylpropyl)acetamide;(R)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(2-phenylpropyl)acetamide;N-(2-chloro-4-methoxyphenethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(R)-N-(1-(4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(4-chloro-2-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;(S)-N-(1-(2-chloro-4-methoxyphenyl)propan-2-yl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;and a pharmaceutically acceptable salt of any one of the above-mentionedcompounds.